Cardiorenal Syndrome: The Role of Neural Connections between the Heart and the Kidneys

Abstract

The maintenance of cardiovascular homeostasis is highly dependent on tightly controlled interactions between the heart and the kidneys. Therefore, it is not surprising that a dysfunction in one organ affects the other. This interlinking relationship is aptly demonstrated in the cardiorenal syndrome. The characteristics of the cardiorenal syndrome state include alterations in neurohumoral drive, autonomic reflexes, and fluid balance. The evidence suggests that several factors contribute to these alterations. These may include peripheral, as well as central nervous system abnormalities. However, accumulating evidence from animals with experimental models of congestive heart failure and renal dysfunction as well as humans with the cardiorenal syndrome suggests that alterations in neural pathways, from and to the kidneys and the heart, including the central nervous system are involved in regulating sympathetic outflow and may be critically important in the alterations in neurohumoral drive, autonomic reflexes and fluid balance commonly observed in the cardiorenal syndrome. This review focuses on studies implicating neural pathways, particularly the afferent and efferent signals from the heart and the kidneys integrating at the level the paraventricular nucleus in the hypothalamus to alter neurohumoral drive, autonomic pathways and fluid balance. Further, it explores the potential mechanisms of action for the known beneficial use of various medications or potential novel therapeutic manipulations for the treatment of the cardiorenal syndrome. A comprehensive understanding of these mechanisms will enhance our ability to treat cardiorenal conditions and their cardiovascular complications more efficaciously as well as thoroughly.

The Cardiorenal Syndrome

The best definition of the cardiorenal syndrome is “disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other”. The cardiorenal syndrome is divided into five sub-categories according to the organ of origin and whether the initiating insult is acute or chronic as identified by Ronco et al¹. Cardiorenal syndrome is associated with increased morbidity and poor clinical outcomes, which leads to a high economic cost as well as a burden on the society, generally². The incidence of impaired renal function is fairly high in chronic cardiovascular diseases in general, and around 40–60% in patients with congestive heart failure (CHF), specifically³. It is estimated that the prevalence of acute kidney injury is around 24–45% in acute decompensated heart failure⁴. Approximately 50% of deaths in all patients with chronic kidney disease (CKD) can be attributed to cardiovascular origins⁵. The combination of CHF with renal dysfunction is strongly predictive of severe adverse clinical outcomes⁶. While the cardiorenal syndrome has been recognized and classified, a comprehensive understanding of the precise interacting mechanisms contributing to sodium and water retention in this syndrome remains elusive.

Congestive heart failure is a pathophysiological state characterized by ventricular dysfunction and associated clinical symptoms including fluid retention. Decreased systolic or diastolic cardiac function results in abnormal hemodynamics, activation of neurohumoral systems and retention of sodium and water^7,8. An impaired ability to excrete a sodium load is commonly seen in patients with CHF^9,10. The clinical picture of advanced stages of CHF is often dominated by the presence of edema and congestion. More importantly, chronic congestion contributes to the further progression of the disease¹¹. CHF and CKD often co-exist^12,13, commonly referred to as the cardiorenal syndrome. The altered renal function has also been suggested to contribute to the pathogenesis of CHF^9,14. The heart is responsible for providing the driving force for the blood to circulate within the body, including to the kidneys, while the kidneys are involved in filtering the circulating blood and maintaining electrolyte balance of the extracellular fluid volume in the body. The maintenance of overall cardiovascular homeostasis is crucially dependent upon the exquisite interactions between the heart and kidneys. Both organs are indisputably critical for survival, tightly linked and inevitably interdependent for normal cardiovascular function. Therefore, it is not surprising that dysfunction in one organ will affect the other. It has been difficult to accurately define the mechanisms of the cardiorenal syndrome because it encompasses a complex series of multifactorial components including physiological, neural reflexes, hormonal, immunological, and biochemical changes over the progression of the disease.

Under normal homeostatic conditions, crosstalk between the heart and the kidneys occurs via the atrial-renal reflexes¹⁵. Classically an increase in atrial pressure decreases renal sympathetic nerve activity (RSNA) and decreases vasopressin release from the posterior pituitary as originally described by the Henry-Gauer Reflex^16,17. It should be noted that although this review is focused on the neural control of the volume reflex, other cardiorenal mechanism^18,19, as well as atrial natriuretic factor²⁰, vasopressin and other neuroendocrine factors may also play a role and interact with the neural component in this syndrome. The consequences of these neural reflexes are to increase the excretion of sodium and water by the kidneys. However, in the setting of CHF, it has been well established that the sodium retention commonly observed in CHF is, in part, due to activation of the efferent renal nerves, or inappropriate renal sympathetic tone despite an increase in blood volume²¹. However, an important gap in our understanding of CHF is that the cause(s) of increased renal efferent sympathetic nerve activity and its role in the overall neurohumoral activation during CHF is not completely understood^22,23. Further, the role of activation of the splanchnic nerves, because of the overall neurohumoral activation which participates in volume redistribution such that it is an important contributor of pulmonary congestion during CHF²⁴, remains to be elucidated. Here we review the interaction among cardiac afferent nerve activation, renal afferent nerve activation, central integration of these signals and consequent efferent cardiac and renal nerve activation. Finally, we review volume redistribution and individual functions of the heart and the kidneys in the cardiorenal syndrome.

The Neural Connection between the Heart and the Kidney

Cardiac sensory afferents to the central nervous system

There is ample electrophysiological and neuroanatomical evidence to demonstrate a neural connection between the heart and the brain. It is well known that cardiac afferent information is transmitted to the central nervous system (CNS). This information initially goes to the nucleus tractus solitarius (NTS) in the brain stem and then is conveyed to higher centers such as the paraventricular nucleus (PVN) in the hypothalamus. There are sensory afferents from the heart that project to the NTS^25,26. Specifically, it has been demonstrated that the commissural portion of NTS receives convergent inputs from peripheral cardiac afferents. This afferent input is thought to play a critical role in mediating the central transmission of the cardiac sympathetic afferent reflex (CSAR)^27,28. It is of importance to note that this portion of the NTS also receives projections from the aortic and carotid chemoreceptors²⁹. The commissural NTS has been shown to contribute to alterations in cardiovascular and chemoreflex function in pathophysiological states³⁰. It is also known that the baroreflex and chemoreflex are predominantly mediated by the dorsal medial and commissural portions of the NTS, respectively. Further, it has been reported that blockade of non-NMDA receptors within the commissural NTS eliminated the pressor and renal sympathetic nerve activity (RSNA) responses to epicardial application of bradykinin³¹. Acute stimulation of cardiac spinal afferents by epicardial application of capsaicin has been shown to significantly decrease the basal discharge of barosensitive neurons in the NTS in anesthetized rats³², indicating that the NTS plays an important role in the processing of the cardiac spinal afferent information input initially before transmitting it to higher centers such as the PVN. The PVN of the hypothalamus is an important integrative site that receives a variety of neural and humoral signals, to regulate sympathetic outflow and extracellular fluid volume³³.

Electrophysiological evidence further demonstrated that chemosensitive neurons were excited by stimulation of the cardiac spinal afferent nerves. Further, epicardial application of capsaicin and bradykinin has been used to effectively stimulate the cardiac spinal afferents³⁴. It has also been reported that more chemosensitive NTS neurons are excited by capsaicin in rats with CHF (84%) compared to sham rats (63%). Cardiac spinal afferents are essential pathways for transmission of cardiac nociception to the CNS during myocardial ischemia. It is now excepted that the CSAR is a sympatho-excitatory reflex, which is initiated by changes in cardiac pressure and/or volume in addition to various endogenous substances such as adenosine, bradykinin, and hydrogen peroxide that are released in the myocardium during the state of myocardial ischemia or CHF^35,36. Myocardial ischemia releases large amounts of metabolites including bradykinin, ATP, prostaglandins and protons that stimulate cardiac afferent nerve endings and increase arterial pressure, heart rate and sympathetic nerve activity.

Stimulation of the CSAR has been demonstrated to increase sympathetic outflow, mean arterial pressure, and heart rate^37–42. Studies from the same laboratory have demonstrated that the discharge of cardiac afferents is increased and CSAR-evoked responses in blood pressure, heart rate and sympathetic nerve activity are exaggerated in rats with CHF^32,39,41,43. On the other hand, acute blockade of cardiac afferent input by local administration of lidocaine, decreased baseline RSNA in dogs and rats with CHF, indicating that the CSAR is tonically activated and contributes to the elevated RSNA in CHF. Furthermore, it has been reported that the sites at which the CSAR is sensitized reside at both the afferent endings as well as during integration at the level of the CNS possibly in the PVN^40,41. There is an excellent review of cardiopulmonary afferents in health and disease states in a recent NIH-directed workshop⁴⁴.

In summary, these findings demonstrate the importance of cardiac afferents affecting overall sympathetic outflow including the renal nerves and thus having their effect on renal function discussed in more detail below. Figure 1 summarizes the potential role of the cardiac afferents via actions within the NTS, PVN and rostral ventrolateral medulla (RVLM) to mediate the regulation of sympathetic outflow to the heart and the kidneys establishing a critical link between the two organs in sympatho-excitatory disease states such as the cardiorenal syndrome.

Figure 1:

Proposed model for the neural and humoral connection between the heart and the kidneys via the central nervous system and the potential therapeutic target sites in cardiorenal syndrome. ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; BBB, blood brain barrier; CSNA, cardiac sympathetic nerve activity; DRG, dorsal root ganglia; GLP-1, glucagon-like peptide-1; IML, intermediolateral cell column; MRA, mineralocorticoid receptor antagonist; NG, nodose ganglion; NTS, nucleus tractus solitarius; PVN, paraventricular nucleus; RSNA, renal sympathetic nerve activity; RVLM, rostral ventrolateral medulla; SGLT2i, sodium-glucose cotransporter 2 inhibitor

Renal sensory input to the central nervous system

Renal sensory receptors

There is a distinct innervation of the kidneys by various sensory afferent nerves⁴⁵. Many sensory nerves are located in the renal pelvis with the highest density in the pelvic wall⁴⁶. Afferent signals from the kidneys transmit two basic modalities, that of mechanoreception and chemoreception^47,48. This information is transmitted to the CNS via the afferent renal nerves (ARN). Mechanoreceptors are mainly observed within the renal parenchyma and in the wall of the renal pelvis⁴⁹. These receptors are activated by changes in intra-renal pressure and respond to occlusion of renal vein or physical distortion of the hilus of the kidney^50,51. Stimulation of renal mechanoreceptors has been demonstrated to increase activity of the ipsilateral renal afferent nerve, while causing a decrease activity in the ipsilateral and contralateral efferent renal nerves^50,52. These responses to activation of the renal mechanoreceptors are eliminated by transection of the spinal cord at the T6 level, indicating that the mechanoreceptor mediated “reno-renal reflex” is reliant on central and/or spinal integration⁵².

The chemoreceptors, designated R1 and R2 receptors, represent the second class of renal sensory receptors, that are activated by the changes in intra-renal “chemical” environment⁴⁷. R1 receptors are stimulated by number of maneuvers such as renal ischemia, arterial and venous occlusion as well as systemic asphyxia⁴⁷. Activation of R1 receptors is concomitant with an increase in efferent renal sympathetic nerves, suggesting an excitatory reflex response⁵³. The R2 receptors are stimulated by either backflow of concentrated urine or infusion of hypertonic sodium chloride or potassium chloride⁴⁷. Similar to the R1 receptor, activation of R2 receptors also produce increases in efferent renal nerve activity and is consistently accompanied by an increase in arterial blood pressure and heart rate⁵³. Spinal transection studies indicate that R2 receptor mediated chemoreceptor reflex is integrated at a spinal level and also influenced by integration at higher sites⁵³. Consistent with these observations there are numerous studies documenting a supra-spinal integration of afferent renal signals as well^54,55.

Renal sensory afferent neural pathways

The neural pathway for the renal sensory afferents to the CNS has been elucidated by a number of studies utilizing anterograde tract tracing of fluorescent dyes⁵⁶, horseradish peroxidase transport^54,57, or pseudorabies virus injected into the kidneys^58,59 as well as electrophysiological experiments^60–62 which indicate that the information carried by renal afferent nerve is communicated to various specific sites within the spinal cord, brain stem and the hypothalamus. Within the spinal cord, the afferent renal nerves (ARN) project to the ipsilateral dorsal horn in laminae I, III-V⁵⁴, where they synapse with interneurons projecting to specific sites within the CNS including the PVN, dictating sympathetic outflow and associated with cardiovascular regulation. Direct monosynaptic projection of the ARN to areas within the brain stem have been demonstrated⁵⁶. ARN have been shown to relay information to the CNS associated with cardiovascular regulation, to the NTS, PVN, RVLM, preoptic area, subfornical organ, and lateral hypothalamus. It is reported that direct electrical stimulation of ARN altered the activity of 197 of the 407 neurons recorded in the hypothalamus, the majority of the units were excited except for 8%, that were inhibited⁶². Thus, it has been suggested that renal afferent nerve signals can elicit both long loop supra-medullary reno-excitatory responses as well as inhibitory reno-renal reflexes^63,64.

Renal afferent nerves consist of mainly slow conducting unmyelinated (primarily C-fibers) with a small population of faster conducting myelinated (A-delta fibers)^65,66. Previously we have observed that the mean onset latency of response in RVLM projecting PVN neurons to ARN stimulation was comparable to those reported in cats⁶⁷ and rats⁶⁸ with a fairly wide range of values⁶⁰. The onset latency of RVLM projecting PVN neurons to high-frequency ARN stimulation was shorter than low-frequency ARN stimulation. The explanation for these finding may be due to the differences in conduction velocities of the different afferent fibers carrying different modalities of information. In terms of electrical stimulation of ARN, activation of renal afferent A fibers is elicited by stimulation with trains of pulses at low-voltage and high-frequency, while renal afferent C fibers is stimulated by trains of pulses at high-voltage and low-frequency^69,70. Generally, it is considered that mechanoreceptor signal is conveyed by the large, myelinated fibers while the chemoreceptor signal is transmitted by the unmyelinated small fibers^65,69,71.

The precise anatomical pathway by which ARN signal is relayed to the PVN is currently not entirely clear. This pathway may involve the NTS and the RVLM in the brain stem, since ARN stimulation alters neuronal firing rates in these areas^70,72. Electrophysiological studies involving stimulation of renal afferent nerves has demonstrated a direct projection from the kidney to the most medial segment of the fasciculatus gracilis and the caudal half of the NTS⁶⁵. Immunofluorescent tracer studies assessing the anatomical connection between the kidneys and medulla also demonstrate that some of the renal afferents project directly to the medulla but do not appear to have such a direct projection to the more rostral areas of the brain. It is estimated that approximately 8% of the total amount of renal afferent projection is typically shown to have a direct projection to the medulla⁵⁶.

Electrical stimulation of ARN in cats affects the activity of medullary neurons in the lateral tegmental field, paramedial reticular nucleus and dorsal vagal complex as well as hypothalamic neurons in the PVN, lateral preoptic area and lateral hypothalamic area⁶². These data provide corroborating electrophysiological evidence for a neural pathway originating in the kidney and transmitting electrical signals to hypothalamic structures such as the PVN implicated in sympatho-excitation and consequently central cardiovascular regulation. Further, our recent studies have demonstrated that there is a neural connection from the PVN to the RVLM that is activated by ARN stimulation⁶⁰. Consistent with these observations it has been shown that there are increased Fos-labelled neurons in the brainstem and the PVN after ARN stimulation. These data suggest that ARN information originating in kidneys is conveyed to several central areas known to be involved in regulating body fluid balance and arterial pressure⁵⁵.

We have previously confirmed renal projections to the hypothalamus by determining the effect of renal denervation (RDN) on changes in noradrenergic function in the hypothalamus^72,73. We observed that depending upon the input from the kidneys there were distinct changes in noradrenergic function that related to changes in arterial pressure and baroreceptor input. The finding of specific changes in noradrenergic function in the hypothalamus after RDN is of interest since brain stem catecholaminergic pathways are known to project directly to both magnocellular and parvocellular neurons in the PVN. This indicates that activation of ARN may alter the activity of neurons in the PVN via ascending catecholaminergic pathways from the brainstem. Electrophysiological studies recording neurons in the PVN that project directly to the neurohypophysis have demonstrated an increase in their rate of discharge during direct stimulation of the ARN⁷⁴. Further, it was shown that the rise in arterial pressure that had a long onset latency and outlasted the duration of ARN stimulation was abolished after administration of vasopressin antagonist⁷⁴. These observations suggested that afferent signals generated by renal receptors can elicit a reflex pathway by which the kidney may alter both sympathetic outflow as well as the release of vasopressin from the neurohypophysis to mediate and influence body fluid and circulatory homeostasis.

There is central integration of ARN signals that elicits an increase in sympathetic tone, which is not exclusive toward the kidneys but also affects other visceral organs^75–77. The ARN sstimulation pressor response, which was locked in time with stimulus duration, was shown to be due to the activation of the sympathetic nervous system^74,78. Signals from renal afferent nerves are reported to participate in spinal feedback loops, termed reno-renal reflexes, whereby afferent activity from one kidney can modulate ipsilateral and contralateral efferent renal nerve activity to regulate diuresis and natriuresis⁴⁵. Such inhibitory reno-renal reflexes have been shown to be blunted in CHF, due to desensitization of renal mechanoreceptors by high circulating levels of angiotensin II and activation of endothelin A receptors^79,80. These authors concluded that dampening of the inhibitory reno-renal reflex may lead to greater sodium retention in CHF.

In summary, the kidneys are known to have dense afferent sensory and efferent sympathetic innervation. This innervation profile strategically positions the kidney as the origin as well as the target of sympathetic nervous system activation⁸¹. Activation of renal afferent nerves sends signals that are integrated centrally and results in an increased sympathetic tone, which is directed toward the kidneys thereby inducing increased sodium retention and renin secretion, as well as toward other visceral organs including the heart to increase heart rate and contractility as well as to the general vasculature resulting in vasoconstriction to cause an overall rise in arterial blood pressure^75–77. It has been well documented that the mammalian kidney comprises of at least two distinct classes of sensory receptors: mechanoreceptors sensitive to changes in renal arterial, venous, or ureteral pressure and chemoreceptors sensitive to changes in the internal milieu of the renal parenchyma. These various sensory receptors within the kidney communicate information to the CNS via the ARN. Therefore, any alterations in renal function or dysfunction in various types of renal diseases such as CKD either acutely or chronically can be transmitted to the CNS to affect the heart and the circulation, thus being very relevant for the cardiorenal syndrome.

Integration of Cardiac and Renal Sensory Afferent Input at the Level of the PVN

The role of the PVN in regulating renal function

Of the five major CNS sites that directly mediate sympathetic outflow⁸², the PVN is the most rostral and the only site in the hypothalamus. This combined with the known role of the PVN in influencing renal nerve activity and vasopressin release, renders the PVN a key site within the forebrain, responsible for mediating altered sympathetic outflow involved in cardiorenal control. The parvocellular neurons within the PVN mediate the neural component of cardiovascular reflexes by specifically influencing the heart and the kidneys. The pre-autonomic neurons in the PVN project to these organs via a single synapse in the intermediolateral cell column (IML) of the spinal cord^{83 84–86}. The PVN is an important integrative site capable of regulating sympathetic drive and influencing cardiovascular function, particularly via its projections to key centers of sympathetic drive, the RVLM and the IML of the spinal cord^{87 88–91}. It has been determined that baseline sympathetic outflow dictated by the RVLM is primarily dependent on the spontaneous activity of pre-autonomic neurons^92,93. Neuroanatomical studies have demonstrated that axons from PVN neurons have terminal sites in close proximity with spinally projecting RVLM neurons, many of which are likely to terminate on sympathetic preganglionic neurons, specifically in the heart and the kidneys^94,95. Electrophysiological studies show that the activity of both RVLM and RVLM/IML projecting PVN neurons are temporally correlated with RSNA thus suggesting that they may contribute to basal sympathetic nerve activity⁹⁶. While the magnocellular neurons are responsible for the humoral component of regulating the action of vasopressin in the distal tubules of the kidneys to influence water reabsorption⁹⁷. Specifically, we have demonstrated that discrete lesions of the parvocellular portion of the PVN with kainic acid altered the renal sympatho-inhibition elicited in response to acute volume expansion⁸⁶. Taken together these findings indicate that the PVN plays a crucial role in the regulation of RSNA under both resting and reflex conditions^84–86. Further, stimulation of the PVN has been demonstrated to induce an increased discharge in several sympathetic nerves, including renal⁹⁸, adrenal⁹⁹, and splanchnic¹⁰⁰. Martin et al. demonstrated that stimulation of PVN raises plasma levels of norepinephrine via a neural mechanism¹⁰¹. It is now well accepted that activation of the PVN produces an increase in overall sympathetic outflow with activation of the renal nerves to influence renal function and sodium excretion.

PVN and chronic heart failure

In the coronary ligation model of CHF in rats, we have observed a significantly increased hexokinase activity (an index of neuronal activity¹⁰²) in the PVN compared to sham-operated controls¹⁰³. Further, we have also observed an increased FosB (fos family gene, indicating chronic neuronal activation¹⁰⁴) staining of the PVN in rats with CHF¹⁰⁵, which is consistent with increased Fra-like (another Fos family gene) staining reported by the others^106,107. These studies indicates chronic activation of the PVN during the CHF condition. In this model of CHF, it has also been shown that norepinephrine is elevated in several forebrain areas, including the PVN and in the brainstem cell groups¹⁰⁸. Further, using direct electrophysiological recording of neurons in the PVN, we have observed an increased firing rate of RVLM projecting PVN neurons in rats with CHF under basal conditions^109,110. This increase firing rate is driven by an enhanced endogenous glutamatergic tone within the PVN of rats with CHF⁸⁷. Furthermore, it of interest to note that the responses of RVLM projecting PVN neurons to baroreflex challenge are reduced, while the responses to osmotic challenge with hypertonic saline are augmented in rats with CHF¹¹⁰.

Currently, there is mounting evidence to substantiate the concept that activation of the PVN neurons that drives sympatho-excitation in CHF is a consequence of an imbalance between the excitatory glutamatergic and angiotensinergic mechanisms and the inhibitory, nitric oxide (NO) and GABA mechanisms^87,111–114. In addition, it has been observed that there is increased circulating levels of cytokines causing the induction of cyclooxygenase-2 expression in the microvasculature of the PVN in CHF. The enhanced proinflammatory cytokines in the PVN have been reported to cause an increase in sympatho-excitation in CHF^{106,115–118}.

As shown above, such an activation of the PVN would increase renal sympathetic activation^119,120. In addition to renal sympathetic activation, there is increased cardiac sympathetic nerve activity as well, often observed as a primary characteristic of patients suffering from CHF^121,122. Prolonged stimulation of the β-adrenergic neurohormonal axis has been shown to contribute to the progression of CHF and mortality in both animal models and in humans^123,124. Measurements of cardiac and renal norepinephrine spillover in CHF patients reflecting cardiac and renal sympathetic tone, indicate that it is increased earlier and to a greater extent than sympathetic nerve activity to other organs in the body^125–127. Data based on direct cardiac and renal sympathetic nerve activity recording in rats with CHF also supports the concept that rats with CHF have markedly higher basal cardiac and renal sympathetic tone than sham rats. Similar specific differential activation of cardiac and renal adrenergic tone but not intestinal tone is demonstrated by studies examining turnover of norepinephrine in various tissues of rats with CHF¹²⁸.

Activation of the PVN by afferent renal nerve stimulation

Electrical stimulation of ARN produces an increase in arterial blood pressure and heart rate¹²⁹. The acute hypertensive response is attributed to the activation of the sympathetic nervous system as well as vasopressin release leading to peripheral vasoconstriction¹²⁹. Previous studies demonstrated that the discharge frequency of putative vasopressinergic magnocellular neurosecretory neurons in the PVN is increased during stimulation of ARN⁷¹ and the activation of specific renal receptors. This study demonstrated that ARN stimulation excites magnocellular neurosecretory neurons in the PVN, since they were antidromically identified to project to the neurohypophysis. This suggests that this renal-paraventricular reflex loop may contribute to the elevated arterial pressure and vasopressin release during ARN activation⁷¹. Consistent with these observations we found that a portion of the non-antidromically identified neurons (from the RVLM) responded to the stimulation of the ARN⁶⁰. This population of PVN neurons may represent the magnocellular neurons that project to the neurohypophysis to elicit vasopressin release observed previously⁷⁴. In addition, ARN stimulation has been shown to elicit an increase in neurons containing Fos-like immunoreactivity in the PVN, indicating that the PVN neurons were activated by extended ARN stimulation⁵⁵. These findings suggest that afferent signals from the kidney provide an important input to the PVN in the coordination of neural and hormonal activity at the level of the PVN, involved with body fluid balance and regulating arterial blood pressure^130,131.

The PVN includes neuroendocrine-related functional neurons that project to the median eminence, posterior pituitary and pre-autonomic neurons that send long descending projections to the RVLM in the brainstem and IML in the spinal cord, regions that dictate final autonomic outflow^132,133. A number of PVN neurons that project to the RVLM, have been demonstrated to correlate temporally with RSNA indicating that they contribute to sympathetic activation to the kidneys⁹⁶. Thus, some of our previous studies concentrated on RVLM projecting PVN neurons. This electrophysiological evidence demonstrated an increase in firing of RVLM projecting PVN neurons in response to electrical stimulation of the ARN. Furthermore, the onset latency of PVN-RVLM neurons was dependent on the frequency of ARN stimulation, suggesting the possibility for transmission of multiple modalities from the kidneys to the PVN. Alternatively, the long latency for the responses in these PVN-RVLM neurons may be due to ARN signal being conveyed via a polysynaptic pathway resulting in a longer transmission time. The exact neuroanatomical pathway by which ARN information is transmitted to the PVN neurons is not entirely clear. A likely path may include the NTS and the RVLM, because single neurons in these specific areas have also been demonstrated to alter their rate of firing in response to ARN stimulation^62,70. Coincidentally, neurons in these same areas have also been demonstrated to relay cardiovascular afferent signal directly to the PVN^134,135. In light of these finding, it is important to understand the utility of the input from the ARN to the pre-autonomic neurons in the PVN and how the PVN integrates signals from the ARN, cardiac afferent nerves and baroreceptor input to regulate overall sympathetic tone. Thus, the longer onset latency in pre-autonomic neurons to ARN stimulation is probably due to both the difference in conduction velocities as well as the polysynaptic pathway from the ARN to the PVN.

Physiologically, the excitatory input via the renal afferents may represent an augmentation of tonic activation from the kidneys or potentially activation of quiescent renal afferents that are activated by a variety of stimuli, such as changes in renal arterial pressure, ischemia, renal venous occlusion, ureteral occlusion, compression of the kidney, and alterations in the ionic composition of the urine in the pelvis because these manipulations have been demonstrated to elicit changes in ARN activity^47,136. However, the direct stimulation of ARN in our previous study did not ascertain a specific modality of the signal from the kidney, only suggesting that both mechanoreceptor and chemoreceptor afferent signals from the kidney are directly transmitted to pre-autonomic PVN-RVLM neurons in the PVN. Chronically enhanced sympatho-excitation is also a characteristic pathological feature of cardiovascular diseases such as CKD, CHF, hypertension, and diabetes. Resting ARN activity is increased in deoxycorticosterone acetate-salt hypertensive rats¹³⁷ and 2-kidney 1-clip CKD mice¹³⁸ and rats with CHF induced by coronary artery ligation²³. Selective afferent RDN performed by capsaicin application improves hypertension¹³⁹, CKD¹⁴⁰ and CHF²³ and mitigates sympathetic nerve overactivity as assessed by direct recording of renal, splanchnic and lumbar sympathetic nerve activities and serum/urinary norepinephrine levels²³.

Several lines of evidence indicate that there is an interaction between the baroreceptor input and the renal afferent input at the level of the hypothalamus⁶¹. Evidence to support interaction between renal afferents and baroreceptor afferents is provided by studies showing that renal afferent fibers project to hypothalamic sites known to influence neurohormonal control of the circulation and fluid balance⁶¹. In addition, it has been reported that a majority of recorded neurons in the hypothalamus that respond to electrical stimulation of ARN also respond to electrical stimulation of arterial baroreceptor afferent fibers⁶². Therefore, it is likely that ARN activation may alter neuronal activation within the hypothalamus, specifically in the PVN which in turn, may modulate the control of neurohormonal activation and thus regulate the circulation. Previously we have shown an interaction between the excitatory stimuli from the renal afferents and inhibitory signals from the baroreceptors in terms of changes in noradrenergic activity within the hypothalamus¹⁴¹. Furthermore, our previous observations also demonstrates that RDN blocks the acute neurogenic hypertension¹⁴², characterized by increased sympathetic outflow, induced by transection of the cervical aortic depressor nerve⁷³; that is, removal of baroreceptor input, specifically. These results showed that removal of tonic renal afferent signals elicited a reduction in elevated sympathetic tone initiated by specific removal of baroreceptor inhibition¹⁴². The results from our ARN stimulation study are consistent with these findings and further provide direct electrophysiological evidence to demonstrate that afferent signals from the kidney activate the same pre-autonomic PVN-RVLM neurons that are inhibited by baroreceptor input and activated by chemoreceptor input. These data, taken together, suggest that there is a direct interaction between the renal afferent signals, baroreceptor input and chemoreceptor input at the level of the pre-autonomic PVN-RVLM neurons to dictate changes in sympathetic outflow. This likely affects both the heart and the kidney. Since in disease conditions known to have enhanced sympathetic outflow such as CHF and CKD, it is conceivable that signals conveyed by renal afferents may contribute an important input in the generation of augmented sympathetic outflow and thus are potentially more amenable to therapeutic approaches, such as catheter-based therapeutic RDN, which has been shown to be effective for the treatment of drug resistant hypertension^143–146. This is elaborated in more detail below.

Previously we have demonstrated that glutamatergic NMDA NR1 receptor mRNA expression and protein levels are significantly increased in the PVN during CHF. These observations in combination with functional assessment of glutamatergic tone in the PVN during CHF indicate that enhanced glutamatergic tone may contribute to the elevated sympatho-excitation observed during CHF⁸⁷. In our previous electrophysiological study, we observed that NMDA activated all the PVN neurons that were sensitive to ARN stimulation, and these responses were attenuated by iontophoretic application of AP5, a glutamate receptor blocker. Therefore, it is conceivable that the enhanced expression of the NMDA receptors and the consequent increase in glutamatergic tone within the PVN may contribute to the enhanced sympatho-excitatory responses in disease states such as CHF and CKD. However, this specific interaction of glutamatergic tone at the level of the PVN for CHF and kidney diseases remains to be investigated.

In summary, these experiments show that variety of sensory signals originating in the kidney directly activate pre-autonomic neurons in PVN which are also influenced by cardiac afferents and suggest that this integration of input from these organs likely contributes to elevated sympathetic nerve activity commonly observed in the cardiorenal syndrome. Furthermore, this afferent renal input is integrated with both baroreflex and the CSAR input at a single neuron level within the PVN to mediate the final output activity of pre-autonomic neurons in the PVN. Thus, it is conceivable that an augmented afferent renal input in disease conditions such as acute or chronic renal failure and/or CHF may be critically involved in interacting with altered baroreflex and CSAR to produce elevated sympathetic nerve activity which is commonly observed in these disease states leading to the deterioration generally observed in the cardiorenal syndrome.

Renal denervation abrogates activation of the PVN during congestive heart failure and chronic kidney disease

The kidneys communicate with various integrative neuronal nodes in the CNS via the renal sensory afferent nerves as outlined above. Intra-renal stimuli or renal pathological conditions, such as ischemia or hypoxia, elicits an increase in ARN activity^147,148. These signals are conveyed by changes in renal sensory afferent nerve activity, directly influencing sympathetic outflow to the kidneys as well as other organs such as the heart and peripheral blood vessels, which are incidentally also modulated by the PVN^149,150. Thus, RDN is likely to be a valuable tool in the treatment of several clinical conditions such as CHF, hypertension and cardiorenal syndrome characterized by increased sympathetic outflow overall, particularly RSNA to the kidney^151–154.

Renal denervation in most experimental forms of hypertension as well as in the drug resistant hypertensive patients has been demonstrated to attenuate arterial pressure and sympathetic activity^143,151,155. Since exaggerated sympatho-excitation is also characteristic of CHF, the efficacy of RDN to reduce sympatho-excitation has been explored in both ischemia-induced and pacing heart models of CHF^156–158 and patients with CHF^159,160. Recent studies utilizing catheter-based therapeutic RDN suggest an improvement of cardiac function in chronic CHF conditions, conceivably by a reduction in tonic renal afferent signals that result in an attenuation of sympatho-excitation^146,161. Thus, it is critically essential to understand the details of the underlying mechanism/s involved in the RDN-mediated decrease in sympatho-excitation. We have previously observed that majority of the PVN neurons (95%) that were sensitive to ARN stimulation were also responsive to baroreflex activation elicited by increases in arterial pressure with phenylephrine. Interestingly, we observed that in a subset of PVN neurons responding to ARN stimulation, all of them (100%) were also responsive to epicardial application of capsaicin, thus, CSAR responsive. Conversely, majority of the PVN neurons that did not respond to ARN stimulation were also not responsive to either baroreflex or CSAR stimulation. These results imply that neurons within the PVN that are sensitive to ARN stimulation are also exquisitely predisposed to both baroreflex as well as cardiac chemoreceptor activation. As outlined above the kidneys communicate with integral structures in the CNS via the renal sensory afferent nerves⁷⁵. Intra-renal stimuli or renal pathologies, such as ischemia or hypoxia, results in an increase in ARN activity^147,148. These results indicate that renal sensory afferent nerve activity directly influences PVN neurons that receive baroreceptor input as well as chemoreceptor input to dictate sympathetic outflow to the kidneys and other organs such as the heart and peripheral blood vessels¹⁴⁹. Thus, RDN which eliminates both the afferent as well as the efferent transmission to the kidneys, is postulated to be valuable in the treatment of several clinical conditions such as CHF as well as acute or chronic renal diseases that are characterized by increased overall sympathetic activation, particularly renal sympathetic nerve activation.

Recently, we have demonstrated that RDN was effective in reducing basal level of lumbar sympathetic nerve activity as well as global sympathetic outflow, as indicated by a reduction in urinary excretion of norepinephrine in rats with CHF¹⁵². In a subsequent study, we found that selective ARN denervation produced a similar reduction in sympathetic outflow in rats with CHF. We interpret these data to indicate that there may be an enhanced tonic level of ARN activity during CHF, which may contribute to activation of pre-autonomic PVN neurons which drive sympatho-excitation. The precise source and modality of this tonic signal from the kidney remains to be explored. Reducing elevated sympatho-excitation is important, as CHF patients with lower levels of plasma norepinephrine have a better prognosis¹⁶². These results indicate that specific ARN denervation may influence the activity of pre-autonomic neurons in the PVN, thereby contributing to the reduction in sympathetic tone.

We observed that both RDN and ARN denervation restored endogenous levels of neuronal NO synthase (nNOS) in the PVN that had been shown to be decreased in rats with CHF¹⁵². Previously, we have also demonstrated that NO (generated by nNOS) mediated sympatho-inhibition from the PVN is blunted in CHF¹¹². Consistent with these observations either, RDN or ARN denervation normalized the blunted lumbar sympathetic nerve activity response to inhibition of endogenous NOS within the PVN observed in rats with CHF¹⁵². We propose that a possible mechanism for the therapeutic effects of RDN or ARN denervation during CHF may be through a tonic effect of renal afferents on NO-dependent mechanisms within the PVN. This is consistent with observations demonstrating the presence of NO synthesizing cells in the PVN interacting with renal sensory information⁵⁸.

RDN in rats with CKD reduced sympathetic tone in the splanchnic and lumbar sympathetic nerves resulting in a decrease in arterial blood pressure¹⁶³. Further, selective ARN denervation in rats with CKD resulted in a decrease in arterial pressure, attenuated the exaggerated renal and splanchnic nerve activity, improved glomerular filtration rate, attenuated proteinuria and renal fibrosis^140,164. These results indicate that renal afferents from the diseased kidneys can transmit a signal to increase sympathetic tone. Chen et al. demonstrated that RDN in rats with CKD normalized GABAergic changes in the NTS and with concomitant improvement in baroreflex function, plasma levels of norepinephrine, glomerulosclerosis, renal tubular injury as well as cardiac changes, suggesting a close link between the potential signals from the kidney affecting cardiac structure and function¹⁶⁵, particularly relevant to the cardiorenal syndrome.

Potential Therapeutic Implications of Manipulating Afferent Signals to the CNS in the Cardiorenal Syndrome

The therapeutic approach to modulate the interaction between the heart and the kidney in the cardiorenal syndrome revolves around the manipulation of sensory input at the level of the heart or kidney or to regulate the integration of signals at the level of the CNS. The central neural sites that regulate cardiovascular function receive information via two distinct pathways, the neural and humoral pathways (Figure 1). The details of the neural pathways that are from the heart and the kidneys are outlined above. The humoral pathway includes the production of messages/signal from the heart and kidneys that are released into the blood and are transmitted to the central sites across areas where the blood brain barrier is weak. Although this review has focused on the PVN it is acknowledged that drugs such as angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIs), and mineralocorticoid receptor blockers (MRAs) may also influence other central sites involved in autonomic function that have a weak blood brain barrier such as subfornical organ, organum vasculosum laminae terminalis and area postrema among others which are beyond scope of this review.

Manipulations of sensory input

Cardiac afferents

Several abnormal cardiovascular reflexes have been reported to be involved in the excessive sympatho-excitation at rest in CHF, including an augmented CSAR. Cardiac afferents are reported to be sensitized in disease conditions such as CHF, hypertension and diabetes. Furthermore, it has been reported that the site at which the CSAR is sensitized reside with the afferent endings. Recently, selective cardiac afferent denervation has been achieved by topical epicardial application of resiniferatoxin, an ultra-potent analog of capsaicin which causes degeneration of TRPV1-expressing neuronal fibers and their cell bodies in rodents as well as translational large animal model^166–168. Resiniferatoxin application induced inhibition of the CSAR associated increase in cardiac and renal sympathetic efferent nerve activities resulting in a discernable reduction in left ventricular end-diastolic pressure, increased cardiac contractile reserve and reduction in cardiac fibrosis in rats with CHF. These authors propose that resiniferatoxin-induced cardiac afferent denervation acts in a cardio-protective manner primarily through inhibition of cardiac sympathetic efferent nerve activity or through inhibition of peripheral sympathetic outflow to vascular beds that affects vascular compliance in CHF state¹⁶⁹. They went on to postulate that ablation of the enhanced CSAR in CHF may offer a novel therapeutic approach in the treatment of CHF for improving cardiac remodeling and overall cardiac function. These data suggest that if it is possible to deliver resiniferatoxin to the surface of the heart using a percutaneous epicardial application and thereby selectively ablate cardiac afferents in patients with CHF it may be possible to improve cardiac function and remodeling. The effect of this procedure on cardiac or renal dysfunction during CKD has not been determined. The utility of this technique in the cardiorenal syndrome remains to be elucidated. Although this is potentially useful, further additional safety studies are required to be rigorously performed before this technique is implemented clinically.

Renal afferents

Resting afferent renal nerve activity has been reported to be greater in rats with CHF, CKD and hypertension compared to normal rats. It has been well documented that angiotensin type 1 receptor/type 2 receptor, mineralocorticoid receptor, and calcium channels in addition to specific transporters involved in diuresis and natriuresis are avidly expressed in the kidneys^170,171. It has also been demonstrated that many antihypertensive drugs, such as ACEIs, ARBs, MRAs, calcium channel blockers and diuretics, target the various corresponding receptors in the kidneys. The actions of these drugs are likely mediated by or contribute to their actions on the renal afferents. The interactions between these therapeutic agents and renal afferents remain to be determined. In addition, it is conceivable that the newer drugs for CHF directly or indirectly act on the renal afferents to potentially modulate overall sympathetic outflow. One prime candidate for this kind of action is the manipulations of sodium-glucose cotransporter 2 (SGLT2) which is localized in the proximal convoluted tubules of the kidney. SGLT2 inhibitors were originally used in patients with diabetes. Since then, they are widely used to treat CHF patients with or without diabetes to alleviate the effects of CHF. Coincidentally, these patients have all the characteristics of the cardiorenal syndrome. Although the mechanism/s of action of SGLT2 inhibitors to improve cardiac function in patients with CHF is not entirely clear, several mechanisms have been proposed for the beneficial effects of SGLT2 inhibitors in CHF, including the direct effects on cardiac energy metabolism. However, in this review we highlight their potential role in the improvement of the cardiorenal syndrome. It is of particular interest that SGLT2 inhibitors mediate glycosuria and natriuresis inducing a reduction in body fluid retention, reducing sympathetic drive and decreasing cardiac overload, ameliorating cardiac function in CHF¹⁷². Interventional studies in patients have shown systemic SGLT2 inhibitors may be an alternative to the treatment of cardiovascular complications of diabetes and CHF¹⁷³.

Recent studies from our laboratory have demonstrated a significant increase in the expression of SGLT2 in the proximal tubules of the kidney in rats with CHF. Consistent with these observations, blocking SGLT2 transporters with dapagliflozin resulted in greater responses of increases in urine flow, sodium excretion and glucose excretion in rats with CHF. Interestingly, removing sympathetic tone to the kidneys by RDN reduced the enhanced expression of renal SGLT2 in rats with CHF. Further, RDN normalized the renal excretory responses to SGLT2 inhibition in rats with CHF. Examining the direct effects of norepinephrine on the expression SGLT2 in renal HEK293 cells, in vitro, demonstrated an increased expression of SGLT2 which was primarily located in the cell membrane fraction. These data suggest that norepinephrine specifically promotes the translocation of SGLT2 from the cytosol to the cell surface. Moreover, there was relatively increased level of SGLT2 on the cell surface compared to cytosol in the kidneys of rats with CHF. Further, after RDN there was decreased membranous levels of SGLT2 while cytoplasmic levels increased in the kidneys of rats with CHF. These findings are consistent with the hypothesis that exaggerated renal sympathetic nerve activation in CHF augments the expression and trafficking of SGLT2 protein to the luminal membrane in proximal tubules resulting in enhanced functional activity of SGLT2 transporters resulting in greater sodium retention in the CHF condition¹⁷¹. Thus, all disease conditions with exaggerated sympatho-excitation such as CHF, CKD, hypertension, and diabetes would be prone to overexpression of SGLT2 related sodium and fluid retention. There are several studies examining the changes in SGLT2 expressions in various disease conditions including the uni-nephrectomised diabetic Otsuka Long-Evans Tokushima Fatty rats, a model of the obese type 2 diabetes^175–177 and spontaneously hypertensive/NIH-corpulent rat, a genetic model of the metabolic syndrome¹⁷⁴. These previous observations are consistent with the suggestion that sympatho-excitation leads to enhanced renal SGLT2 protein expression commonly associated with metabolic disorders induced by high glucose and high-fat diet, all known to have renal dysfunction as well as CHF, possibly including CKD. It is of interest to note that an acute inhibition of SGLT2 does not produce a change in arterial pressure or heart rate while exhibiting increases in urine flow and sodium excretion, indicating a lack of compensatory sympatho-excitation that may occur in response to an acute reduction in fluid volume. Taken together these observations are are congruent with previous studies in humans and various animal models of diabetes and CKD, and also appear to be favorable approach in the treatment for CHF condition^178,179.

Although the specific underlying molecular mechanisms in the regulation of renal SGLT2 are not completely elucidated, it has been postulated that SGLT2 expression is modulated by glucose levels in the glomerulus via intracellular cAMP and PKA signaling pathways^180,181. In addition, inflammatory cytokines such as interleukin-6 and tumor necrosis factor-α are known to upregulate SGLT2¹⁸². Incidentally, norepinephrine also has been shown to stimulate interleukine-6 secretion in human kidney proximal tubule cell line¹⁸³. Furthermore, renal nerves have been demonstrated to facilitate renal inflammation due to activation of T-cells and increase inflammatory cytokines^184,185. Interestingly, a common pathophysiological property in both CHF and CKD is renal inflammation^186–188. Thus, it may well be that enhanced sympatho-excitation which is commonly observed in both CHF and CKD results in renal inflammation which mediates enhanced SGLT2 expressions resulting in enhanced renal retentive mechanisms. The precise interactions between renal inflammation, SGLT2 and the role of the renal nerves (afferent and/or efferent) in CHF and CKD remains to be explored.

As discussed above RDN has been introduced as a novel therapy to treat drug resistant hypertension^189,190. It is thought to be another approach to directly modulate the sympathetic nervous system. However, RDN interrupts both the afferent inputs to the CNS from the kidney as well as the efferent outputs from the CNS to the kidney, resulting in suppression of sympathetic outflow and eliciting beneficial effects in both hypertension and CHF. It would be worthwhile to assess if the efficacy of renal targeted drugs is enhanced by RDN and determine the role of the afferent and efferent nerves in improving the therapeutic efficacy of these pharmacological treatments for CHF, hypertension, and CKD. One such example is the use of RDN to normalize renal excretory responses to SGLT2 inhibitor in CHF. The results with RDN in CHF discussed above indicate that tonic renal sympathetic nerve activation promotes enhanced function of SGLT2 in CHF. The results of RDN in non-CHF controls suggest that RDN does not affect the expression and function of SGLT2 in normal healthy condition. Further, selective ARN denervation also improved the central activation of the PVN as well as the enhanced sympatho-excitation normally observed during CHF suggesting that if selective ARN denervation can be achieved in patients with CHF or CKD, this would be a potentially novel and efficacious therapy for all forms of the cardiorenal syndrome. Experimental animal and human mechanistic studies examining SGLT2 inhibition have also reported other pathways that are closely linked with kidney protection, specifically those related to natriuresis^191,192. It is of interest to note that the efficacy and safety of RDN have been shown to date in clinical trials with non-CKD patients and the prospective, randomized, sham-controlled clinical trial examining the effect of RDN in CKD (RDN-CKD Study [https://www.clinicaltrials.gov; unique identifier: NCT04264403]) that is currently ongoing and will provide important information about the usefulness of RDN in CKD.

There is also ample experimental and clinical evidence that shows a strong association between “sympathetic hyperactivation” and acute ischemic-mediated arrhythmias. It is of interest to note that surgical or chemical RDN has been shown to have beneficial remodeling of electrophysiological characteristics that translate into a decrease in ventricular arrhythmia after myocardial infarction¹⁹³. Research in animal models indicates several potential atrial antiarrhythmic effects of RDN including heterogeneous conduction, shorter and less dispersed refractoriness, less fibrosis, reduced neurohumoral activation, less sympathetic nerve sprouting, and diminished stellate ganglion activity^194–196. Interestingly ablation of aorticorenal ganglion or RDN was protective against ventricular arrhythmias and sudden death after myocardial infarction in pigs¹⁹⁷. A randomized clinical trial also shows the antiarrhythmic effect of RDN on atrial fibrillation. To “evaluate renal denervation in addition to catheter ablation to eliminate atrial fibrillation” (ERADICATE-AF) trial has shown that RDN added to pulmonary vein isolation enhanced long-term antiarrhythmic efficacy compared with pulmonary vein isolation alone in hypertensive patients with atrial fibrillation¹⁹⁸. Further, a systematic review of RDN for the management of refractory ventricular arrhythmias suggests that RDN is an effective treatment of refractory ventricular arrhythmias¹⁹⁹. Thus, RDN has been described as an additional neuromodulatory treatment for recurrent atrial fibrillation, ventricular arrhythmias and electrical storm.

To date, cardiovascular outcome studies show that glucagon-like peptide 1 receptor (GLP-1R) agonists reduce cardiovascular events including myocardial infarction, and also prevent the progression of CKD in type 2 diabetic patients. Consistent with these observations a number of preclinical studies in animals demonstrate cardioprotective actions of GLP-1R agonists in experimental models of ischemic cardiac injury and hypertensive cardiomyopathy^200,201. However, the mechanisms linking GLP-1R activation and cardio protection are not fully understood. GLP-1R agonists rapidly increase urinary sodium excretion in preclinical studies, actions mediated through the canonical GLP-1R. One possible mechanism is thought to be mediated by natriuresis leading to a reduction in plasma volume without adverse activation of the sympathetic system. Previously we have shown that GLP-1 activates ARN to increase efferent RSNA which negates the diuresis and natriuresis as a negative feedback mechanism in normal rats²⁰². Interestingly, the natriuretic actions of GLP-1R agonists are blunted in rats with experimental CHF. The response of an increase in afferent renal nerve activity to intrapelvic injection of GLP-1 was enhanced in CHF. Further, the increase in RSNA by intravenous infusion of GLP-1 was two-fold higher in CHF compared to Sham. Consistent with these observations selective afferent RDN restored natriuretic actions of GLP-1R agonists in rats with CHF^{202 203}. These observations provide potential insight for the use of GLP-1R agonists to reduce cardiovascular events and prevent the progression of CKD in patients with the cardiorenal syndrome.

Manipulations of humoral input

It is of interest to note that, some of the antihypertensive drugs, that target the central renin-angiotensin system such as ACEIs, ARBs, ARNIs, and MRAs, utilize the areas of weak blood brain barrier to enter the brain for their actions²⁰⁴. There is a distinct and discrete renin-angiotensin system in various brain areas that control cardiovascular and renal function, such as the PVN and the RVLM, which is independent of the peripheral circulatory renin-angiotensin system. Consistent with these observations, angiotensin type 1 receptor, angiotensin type 2 receptor, mineralocorticoid receptors and renin receptors are expressed in these brain areas. It has been reported that the brain renin-angiotensin system contributes to the regulation of sympathetic outflow^114,205. Evidence shows that activation of angiotensin type 1 receptor in the hypothalamus and the brainstem exist upstream of increased reactive oxygen species and decreased nitric oxide augments sympathetic outflow¹¹⁴. It has been shown that activation of the renin receptor produces angiotensin II in the brain resulting in increases in arterial blood pressure. Angiotensin II administration within the PVN has also been demonstrated to increase RSNA¹¹⁴. Thus, manipulation of the central renin-angiotensin system, potentially within specific discrete sites may provide a novel and efficacious treatment for the modulation of sympathetic outflow during cardiorenal syndrome.

Another factor, neprilysin which is primarily expressed in the kidneys and is known to degrade angiotensin II and natriuretic peptides may have an efficacious use in the treatment of the cardiorenal syndrome. Currently, a new class of drugs, the ARNIs have been developed for the treatment of CHF and hypertension. ARNIs inhibit neprilysin activity in the kidney to increase circulating natriuretic peptides and reduce the levels of angiotensin II. The mechanism of action and interactions with the sympathetic nervous system would provide a novel treatment modality. The use of these drugs to elicit improvement in the cardiorenal syndrome remains to be explored.

Summary and Conclusion

Although for ease of explanation we have presented the above discussion as a forward flow of information from sensory systems in the heart and the kidneys to the extended hypothalamus, particularly the PVN, with the autonomic outflow to the heart and the kidney, the reality is not so straightforward. All the regions discussed above, and several others, send projections to each other allowing for the possibility of feedback and crosstalk amongst systems. Furthermore, most of these regions have been implicated in the control of multiple cardiovascular disease conditions, including CHF, CKD, hypertension, metabolic syndrome, or diabetes. Indeed, based on neuroanatomical interconnections, strong electrophysiological evidence, and overlapping patterns of cardiac and renal activation across CHF and CKD, the existence of a neural connection for ‘cardiorenal syndrome’ is proposed. This network is highly interactive across the CNS, particularly at the level of the PVN, providing a useful framework for comparative analysis and future studies. This perspective can also prove to be useful for conceptualizing the regulation of neural circuits in the cardiorenal syndrome. Through this lens, changes in the cardiac milieu under conditions of CHF act to fine tune connections and activity patterns across the sympathetic outflows and thus modulate the shift in renal function. In contrast, the likelihood of a particular change in the renal parenchyma due to kidney disease can influence neural activity in the heart. Indeed, as discussed above, changes in the heart in CHF regulate a myriad of structural, electrophysiological, and neural elements which converge to augment or attenuate circuit activity and sympathetic output to the kidney (Figure 1). Similarly, changes in sensory input from the kidney in CKD enhance sympathetic activity to the heart resulting in cardiac dysfunction. Recent and continued development of increasingly powerful tools is enabling unprecedented dissection of neuronal sub-circuits with capabilities to activate or abrogate neural signals to the brain from peripheral organs rather precisely. With this enhanced understanding of the neural circuits between the heart and the kidneys, we have presented a foundation to develop potential therapeutic interventions for the cardiorenal syndrome.

In conclusion, the altered functions of the heart and the kidneys in the cardiorenal syndrome is intimately tied to the regulation of the sympathetic nervous system. This process that integrates visceral inputs from various peripheral sites, including cardiac and renal afferents in the CNS, to determine sympathetic outflow is critically involved in the functions of both organs under normal conditions and the various manifestations of the cardiorenal syndrome. Antihypertensive or CHF drugs potentially act on the various sites within the central pathways that modulate sympathetic outflow or peripheral sites and thus affect the severity of the cardiorenal syndrome (Figure 1). Further basic and clinical studies are needed to explore the potential targets and roles in the processing of the afferent input from the heart and kidneys in the regulation of the sympathetic nervous system by various drugs used to treat hypertension, CHF, CKD and diabetes for their synergistic effects as well as the effect of RDN in the cardiorenal syndrome.

Non-standard Abbreviations and Acronyms

ACEIs

angiotensin converting enzyme inhibitors

ARBs

angiotensin receptor blockers

ARN

afferent renal nerves

ARNIs

angiotensin receptor neprilysin inhibitors

CHF

congestive heart failure

CKD

chronic kidney disease

CNS

central nervous system

CSAR

cardiac sympathetic afferent reflex

GLP-1R

glucagon-like peptide 1 receptor

IML

intermediolateral cell column

MRAs

mineralocorticoid receptor blockers

NTS

nucleus tractus solitarius

NO

nitric oxide

nNOS

neuronal nitric oxide synthase

PVN

paraventricular nucleus

RDN

renal denervation

RSNA

renal sympathetic nerve activity

RVLM

rostral ventrolateral medulla

SGLT2

sodium-glucose cotransporter 2