Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2015 Mar 1.
Published in final edited form as: Curr Opin Nephrol Hypertens. 2014 Mar;23(2):122–129. doi: 10.1097/01.mnh.0000441053.81339.61

Direct regulation of ENaC by bradykinin in the distal nephron. Implications for renal sodium handling

Mykola Mamenko 1, Oleg Zaika 1, Oleh Pochynyuk 1
PMCID: PMC4114036  NIHMSID: NIHMS607874  PMID: 24378775

Abstract

Purpose of review

Locally produced peptide hormones kinins, such as bradykinin, are thought to oppose many of the prohypertensive actions of the renin–angiotensin–aldosterone system. In the kidney, bradykinin, via stimulation of B2 receptors (B2R), favors natriuresis mostly due to the inhibition of tubular Na+ reabsorption. Recent experimental evidence identifies the epithelial Na+ channel (ENaC) as a key end effector of bradykinin actions in the distal tubular segments. The focus of this review is the physiological relevance and molecular details of the bradykinin signal to ENaC.

Recent findings

The recent epidemiological GenSalt study demonstrated that genetic variants of the gene encoding B2R show significant associations with the salt sensitivity of blood pressure. Bradykinin was shown to have an inhibitory effect on the distal nephron sodium transport via stimulation of B2 receptor-phospholipase C (B2R-PLC) cascade to decrease ENaC open probability. Genetic ablation of bradykinin receptors in mice led to an augmented ENaC function, particularly during elevated sodium intake, likely contributing to the salt-sensitive hypertensive phenotype. Furthermore, augmentation of bradykinin signaling in the distal nephron was demonstrated to be an important component of the natriuretic and antihypertensive effects of angiotensin converting enzyme inhibition.

Summary

Salt-sensitive inhibition of ENaC activity by bradykinin greatly advances our understanding of the molecular mechanisms that are responsible for shutting down distal tubule sodium reabsorption during volume expanded conditions to avoid salt-sensitive hypertension.

Keywords: collecting duct, connecting tubule, renal kallikrein–kinin system

INTRODUCTION

Proper control of systemic blood pressure (BP) is a fundamental clinical problem. Approximately 1 billion humans have hypertension and accompanying cardiovascular diseases worldwide [1]. We now recognize that the renin–angiotensin–aldosterone system (RAAS) plays a major role in the pathogenesis of hypertension [2]. Inhibition of the RAAS at multiple levels is the backbone of contemporary therapeutic strategies to reduce BP in patients [3]. Currently, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are among the most prescribed antihypertensive drugs and are the first choice to treat cardiovascular diseases, chronic heart failure, arrhythmias, and a number of other conditions [3,4]. Importantly, substantial experimental and clinical evidence suggests that ACEIs and many ARBs not only interfere with RAAS activation but also promote beneficial actions of kinins on vascular tone and renal sodium excretion in rodent animal models and in patients [5–7]. In this review, we summarize recent findings related to signaling and physiological relevance of the natriuretic actions of kinins in the distal nephron.

RENAL KALLIKREIN–KININ SYSTEM DECREASES DISTAL TUBULE SODIUM TRANSPORT

The local hormone peptides kinins, such as bradykinin, are principal effectors of the kallikrein–kinin system (KKS). Bradykinin is produced from the inactive precursor molecule kininogen following cleavage by the serine protease kallikrein [8]. Bradykinin interacts with G-protein-coupled B1 and B2 receptors (B1R and B2R, respectively) to stimulate numerous intracellular signaling cascades [9,10]. The biological effects of bradykinin are mediated mainly through the B2R which are constitutively expressed in smooth muscles, neurons, vascular endothelium, and kidney epithelial cells [11]. KKS is envisioned as a natural counterbalance of the RAAS. At the whole body level, KKS possesses multiple beneficial actions which reduce excessive burden on the cardiovascular system in response to RAAS activation [12]. This includes vasodilation, reduction of oxidative stress, stimulation of NO production, and augmentation of urinary sodium excretion [12–14]. Importantly, dysfunction KKS components, including kininogen [15], kallikrein [16], and B2R [17,18], causes hypertension in animal genetic models when sodium intake is elevated. Low urinary kallikrein levels are consistently found in individuals with essential hypertension [19]. A polymorphism in the human B2R gene (+9,+9) is linked to an increased cardiovascular risk and higher systolic BP [20]. In contrast, transgenic mice and rats overexpressing either human kallikrein (KLK1) or B2R genes are permanently hypotensive [21,22]. Altogether, this strongly supports the concept that the functional status of KKS is a critical component of BP control.

In addition to the well-documented actions in controlling vascular tone, kinins are also important regulators of renal sodium handling [23,24]. Interstitial fluid bradykinin levels are reported to be in the 10–100 nM range in both cortex and medulla regions of the rat kidney [25]. These concentrations are considerably higher than those present in the bloodstream [26] and more than sufficient to effectively stimulate B2R [27,28]. In perfused rat kidneys, acute pharmacological inhibition of B2 receptors with HOE-140 (icatibant) decreased urinary Na+ excretion without altering glomerular filtration rate (GFR) or renal blood flow [24]. Importantly, high dietary sodium intake potentiates the natriuretic actions of renal KKS [29] and consistently augments urinary excretion of bradykinin and kallikrein [30]. This salt dependence indicates that the principal action site for the KKS in the renal tubule is likely restricted to the distal segments.

The distal part of the renal nephron, which includes the connecting tubule (CNT) and the cortical collecting duct (CCD), is recognized as playing a critical role in the negative feedback pathway that fine-tunes renal sodium excretion to match dietary Na+ intake [31■]. Sodium reabsorption here is under fine control by the RAAS to maintain systemic fluid volume and set chronic BP. Activity of the apically localized epithelial Na+ channel (ENaC) determines the electrogenic Na+-reabsorption in the distal nephron [31■]. ENaC is uniquely positioned to respond to changes in systemic Na+ balance [32,33]. Both aldosterone [34] and Ang II [35] have stimulatory actions on ENaC that are essential to prevent renal sodium losses, particularly during volume contractions. The physiological importance of ENaC in the regulation of BP in humans is emphasized by the inheritable forms of hypertension (Liddle’s syndrome) resulting from gain-of-function mutations of the channel [36–41]. Loss-of-function mutations, in contrast, lead to salt wasting and low BP (pseudohypoaldosteronism type I) [39,40].

Although the RAAS-mediated endocrine control of ENaC activity provides a mechanistic explanation of augmented Na+ reabsorption in the distal nephron during dietary sodium restriction, the concept of ENaC inhibition during volume-expanded states is just beginning to emerge. Effective suppression of ENaC activity during high sodium intake is viewed as an important regulatory mechanism that allows avoiding excessive sodium retention and salt-sensitive hypertension. An inability to decrease ENaC activity contributes to the development of elevated BP in humans [42] and in many salt-sensitive hypertensive animal models, such as salt-sensitive Dahl rats [43,44]. Recent experimental evidence strongly suggest that KKS, and specifically bradykinin, is essential for the proper regulation of ENaC activity by dietary salt intake particularly during volume expanded states [45■■,46].

SIGNALING MECHANISMS FOR THE REGULATION OF EPITHELIAL Na+ CHANNEL-MEDIATED SODIUM REABSORPTION BY BRADYKININ

Immunostaining and in-situ hybridization studies suggest that all components of the renal KKS are predominantly localized to the distal part of the renal nephron. Specifically, kallikrein is actively synthesized in the CNT, whereas kininogen and B2 receptors are expressed mainly in the collecting duct [47,48]. Furthermore, expression of KKS components and B2R is intimately coordinated with the terminal differentiation of the distal nephron during nephrogenesis [49]. This suggests that the renal KKS is well positioned to control the function of ENaC, which is also expressed in these tubular segments. However, the initial studies probing bradykinin’s effect on sodium transport in the distal nephron did not yield consensus. Bradykinin inhibited the amiloride-sensitive component of conductive Na+ uptake at the apical membrane in rabbit collecting duct cells [50]. Amiloride is a fairly specific ENaC blocker. In contrast, basolaterally applied bradykinin inhibited net sodium absorption in perfused rat CCDs without changes in transepithelial voltage, pointing to its electroneutral ENaC-independent nature [51]. Using patch clamp electrophysiology to monitor single channel function in real time, our group recently demonstrated that nanomolar concentrations of bradykinin acutely and reversibly decrease ENaC activity in freshly isolated split-opened distal nephrons as well as in cultured mpkCCDc14 cells [45■■,46]. This strongly suggests that ENaC-mediated sodium reabsorption is indeed a target of the renal KKS. The absence of changes in transepithelial voltage during bradykinin treatment in perfused CCDs [51] can be explained by the observation that bradykinin also decreases net Cl− absorption in the perfused CCDs [52]. It is possible that changes in transepithelial voltage due to electrogenic ENaC-mediated sodium reabsorption may be compensated by respective changes in Cl− uptake. Indeed, coordination of Na+ and Cl− transport in the distal part of the renal tubule is described in literature. For example, a recent study shows that overexpression of the chloride transporter pendrin, in intercalated cells of the distal nephron leads to respective activation of ENaC-mediated sodium reabsorption without significant changes in transepithelial voltage [53].

We have also gained substantial knowledge concerning the signaling determinants of bradykinin signaling in native distal nephron cells (Fig. 1). Using a combination of pharmacological and genetic approaches, it was shown that stimulation of the B2R-Gq/11-PLC pathway is central for bradykinin-mediated inhibition of ENaC in split-opened murine distal nephrons [45■■,46]. This leads to a diminished activity of the channels (i.e., open probability, Po) rather than to a decreased number of functional channels residing on the apical plasma membrane. Consistently, mice lacking bradykinin receptors have unchanged ENaC levels but inappropriately augmented ENaC Po in the distal nephron cells [45■■]. Interestingly, dynamic changes in ENaC Po by bradykinin signaling in the distal nephron is likely determined by the availability of a signaling phospholipid, PI(4,5)P2, in the apical plasma membrane, which is rapidly degraded in response to PLC activation [46]. PI(4,5)P2 is known to acutely regulate ENaC Po via direct interaction and possible binding to the positively charged domains within intracellular N-termini of β-ENaC and γ-ENaC subunits [54]. In addition, activation of bradykinin signaling is known to stimulate NO production via endothelial nitric-oxide synthase-dependent pathways in cortex kidney slices [55], augment production of cytochrome P450 derivatives in perfused rat kidney [56], and, similarly, the PLA2 signaling cascade in rabbit CCD cells [57]. All these pathways can also exert inhibitory actions on ENaC [58,59]. It remains to be further determined whether they play a notable role in bradykinin-mediated regulation of ENaC.

FIGURE 1.

FIGURE 1

Open in a new tab

Intracellular signaling pathway implicated in the regulation of ENaC activity by bradykinin in the distal nephron. Bold arrows represent signaling pathways supported by direct experimental evidence; thin arrows indicate additional possible mechanisms of regulation. NH2 and COOH demonstrate amino-termini and carboxyl-termini of ENaC subunits, respectively. AA, arachidonic acid; B2R, bradykinin type 2 receptor; CYP, cytochrome P450; EET, epoxyeicosatrienoic acids; ENaC, epithelial Na+ channel, Gq/11, heterotrimeric G protein Q/11 subtype; NO, nitric oxide; PIP2, phosphatidylinositol 4,5-bisphosphate; PLA2, phospholipase A2; PLC, phospholipase C.

It should also be noted that the effects of the renal KKS on Na+ transport in the distal nephron are likely more complex and may occur independently of bradykinin. Tissue kallikrein can proteolytically cleave ENaC at the site of another serine protease, prostasin to augment channel activity [60■,61]. This may facilitate ENaC activation during states with elevated circulating levels of aldosterone such as low Na+ and high K+ dietary intakes [60■]. However, the physiological relevance of this regulation is still unclear as overexpression of human kallikrein in rats and mice causes hypotension [21,62]. Similar dual actions on Na+ handling in the kidney have been reported for prostaglandins. Despite the fact that renal prostaglandins cause natriuresis and diuresis [63], they also play a critical role in promoting renin secretion [64]. It is possible that such opposite effects serve to partially balance each other, thus protecting from extreme disturbances in kidney function.

SALT SENSITIVITY OF BRADYKININ ACTIONS ON EPITHELIAL Na+ CHANNELS IN THE DISTAL NEPHRON

The epidemiological GenSalt study demonstrated that genetic variants of the bradykinin receptor B2 gene (BDKRB2) showed significant associations with salt-sensitivity phenotypes, even after adjusting multiple testing among a large and homogeneous sample of Han Chinese families [65■■]. Consistently, mice lacking B2R develophypertension when challenged with elevated sodium intake and may have mildly increased BP during unstressed conditions [17,18,66]. Several studies point to an altered vasoconstriction that might be a cause for the elevated BP [18,67]. However, experimental evidence also demonstrates a critical contribution of compromised renal sodium handling in the pathology. Thus, acute inhibition of B2R increases fractional Na+ excretion without noticeable changes in GFR and inner medullary and cortical blood flow in rats fed normal but not low sodium diet [24]. This suggests that renal kinins tonically decrease sodium transport in the terminal segments of nephron during normal physiological conditions [68]. Furthermore, genetic or pharmacological interference with B2R function exacerbates BP elevations and reduces cumulative urinary sodium excretion during conditions of mineralocorticoid excess [69,70]. Finally, tissue kallikrein deficiency also leads to augmented aldosterone–salt-induced hypertension, which can be at least partially explained by renal sodium retention because of the enhanced distal nephron sodium reabsorption [71■]. In a good agreement with these studies, our group recently demonstrated that dysfunction of the KKS due to genetic deletion of both bradykinin receptors (B1R and B2R) increases basal ENaC Po compared with the values in wild-type mice during regular sodium intake [45■■]. The difference in basal ENaC Po was augmented during elevated Na+ intake and negated during Na+ restriction. At the same time, the stimulatory actions of exogenously administered mineralocorticoids on ENaC activity were similar in wild-type and mutant mice indicating nonredundancy of bradykinin actions on ENaC [45■■]. Overall, these observations strongly suggest that bradykinin signaling plays an important physiological role by decreasing ENaC activity in the aldosterone-sensitive distal nephron during euvolemic and volume expanded states to avoid excessive sodium retention. It is conceivable that genetic deletion of bradykinin receptors recapitulates the state of gain-of-function mutations in ENaC causing hypertension in humans [36,37]. However, taking into consideration that multiple factors play a role in the hypertensive phenotype in KKS dysfunction, the exact contribution of the augmented ENaC-mediated sodium reabsorption requires further careful examination.

REGULATION OF EPITHELIAL Na+ CHANNEL ACTIVITY BY BRADYKININ CONTRIBUTES TO THE NATRIURETIC EFFECT OF ANGIOTENSIN CONVERTING ENZYME INHIBITION

It is known that ACE activity constitutes one of the major pathways responsible for the cleavage and degradation of kinins [12]. Interestingly, in-vitro studies suggest ACE is approximately 30 times more potent in cleaving kinins than in producing Ang II from Ang I [47,72]. In the kidney, sufficient ACE activity is present at the apical plasma membrane of principal cells in the distal nephron [73,74]. This suggests that the functional status of ACE determines the extent of ENaC inhibition by bradykinin.

Acute ACE blockade with captopril greatly augments elevations of [Ca2+]i in murine distal nephron cells in response to bradykinin indicating a higher level of B2R activation [45■■]. Moreover, this causes substantially stronger inhibition of ENaC activity by smaller concentrations of bradykinin in split-opened distal nephrons of mice [45■■]. Such augmentation of bradykinin signaling could possibly be explained by the close association of ACE with B2R, as has been reported for different cell types [75]. This leads to a decreased actual concentration of the agonist in the vicinity of the receptors because of the tonic kininase activity of ACE. Alternatively, ACE inhibitors can directly interact with B2R allosterically enhancing function of the receptor [76].

The observation that bradykinin-mediated inhibition of ENaC is controlled by ACE, suggests that augmented bradykinin signaling in the distal nephron can contribute to the natriuresis and decreased BP promoted by ACE inhibition. Consistent with this, B2R inhibition significantly attenuates the hypotensive effect of the ACE inhibition in both normotensive and hypertensive individuals [7]. Using patch clamp electrophysiology in freshly isolated mouse distal nephrons, our group demonstrated that chronic ACE blockade with captopril leads to a markedly diminished basal ENaC activity in the distal nephron cells of mice kept on normal sodium intake [45■■]. Importantly, genetic ablation of bradykinin receptors virtually eliminates this inhibition, pointing to a dominant role of bradykinin signaling. This was also associated with blunted natriuresis in response to captopril in mutant mice [45■■]. However, the precise contribution of the amiloride-sensitive (i.e., ENaC dependent) component was not directly assessed.

Interestingly, regulation of bradykinin levels by ACE may represent only a part of a more complex interaction between renal KKS and the intratubular renin–angiotensin system (RAS). Indeed, all components of the functional local RAS are present in the distal nephron. Principal cells in the CNT and CCD abundantly express renin [77,78] that, in turn, cleaves angiotensinogen synthesized by the proximal tubule to Ang I [79]. ACE is present at the apical membrane of distal nephron cells allowing paracrine generation of Ang II from Ang I [73,78,80]. We now recognize a critical role of the intrarenal RAS in the development of excessive sodium retention during different pathological conditions such as salt-sensitive hypertension and diabetes mellitus [78,81,82]. Kidneys have enormous capacity to produce Ang II locally. The renal tubules and interstitial compartments contain up to 1000-fold higher levels of Ang II compared with that present in plasma indicating high ACE activity [83,84]. Interestingly, genetic deletion of ACE in the kidney drastically diminishes the hypertension induced by Ang II infusion and prevents the activation of sodium transporting systems, including ENaC, in the loop of Henle and distal nephron [85■]. Furthermore, AT1R and B2R are reported to be coupled at the functional and transcriptional levels in distal nephron cells. Specifically, augmented responses to bradykinin are reported in inner medullary collecting duct cells treated with Ang II [86]. In contrast, B2R mRNA levels are significantly decreased in mice lacking AT1R [86]. Thus, it is reasonable to propose that this spatial co-localization of KKS and RAS in the distal nephron cells allows intricate interactions between the two systems in setting ENaC-mediated sodium reabsorption in response to systemic stimuli. Concomitantly with the actions of aldosterone, distal tubular RAS is essential to increase ENaC-mediated Na+ reabsorption during dietary sodium restriction. In contrast, a dominant role of the KKS becomes apparent upon volume-expanded states promoting natriuresis and protecting from excessive salt conservation (Fig. 2). A thorough understanding of this process will allow precise control of salt and water urinary excretion enabling delicate but effective correction of circulating volume.

FIGURE 2.

FIGURE 2

Open in a new tab

Principal scheme of interaction between the kallikrein–kinin and renin–angiotensin systems in the distal nephron during different salt intakes. ACE, angiotensin converting enzyme; Ang I, angiotensin I; Ang II, angiotensin II; AT1R, angiotensin type 1 receptor; B2R, bradykinin type 2 receptor; ENaC, epithelial Na+ channel; MR, mineralocorticoid receptor. Dotted arrows represent inactive mechanisms of ENaC regulation under particular sodium intake.

CONCLUSION

Recent experimental and clinical efforts have greatly advanced our understanding of the mechanisms and physiological relevance of kinin actions on ENaC-mediated sodium transport in the distal nephron. Bradykinin, via stimulation of B2R, exerts tonic inhibitory actions on ENaC activity by reducing single channel capacity to conduct Na+. Disruption of this regulation in animal genetic models leads to overactive ENaC that is detrimental under sodium-loaded conditions. Consistently, genetic variations in the gene encoding B2R correlate with susceptibility to develop salt-sensitive hypertension in patients. Bradykinin actions on ENaC appear to significantly contribute to the natriuresis promoted by ACE inhibition. Thus, it is likely that genetic polymorphism in genes encoding B2R and other functional components of KKS may predict the efficiency of antihypertensive blockade of RAAS in patients. Future studies are needed to probe this possibility.

KEY POINTS.

  • Renal KKS inhibits sodium reabsorption and specifically ENaC activity in the distal nephron during normal and high dietary sodium intake.

  • Bradykinin acutely inhibits ENaC open probability in native distal nephron cells via stimulation of B2 receptors, activation of phosholipase C, followed by the depletion of PI(4,5)P2 levels.

  • Augmented bradykinin signaling in the distal nephron contributes to the natriuresis promoted by ACE inhibition.

Acknowledgements

None.

The research program is supported by the NIH-NIDDK DK095029 (to O. P.), andAHA-GIA-13GRNT16220002 (to O.P.)

Footnotes

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

■ of special interest

■■ of outstanding interest

  • 1.Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217–223. doi: 10.1016/S0140-6736(05)17741-1. [DOI] [PubMed] [Google Scholar]
  • 2.Zaman MA, Oparil S, Calhoun DA. Drugs targeting the renin-angiotensin-aldosterone system. Nat Rev Drug Discov. 2002;1:621–636. doi: 10.1038/nrd873. [DOI] [PubMed] [Google Scholar]
  • 3.Seva PB, van der LN, Verdonk K, et al. Key developments in renin-angiotensin-aldosterone system inhibition. Nat Rev Nephrol. 2013;9:26–36. doi: 10.1038/nrneph.2012.249. [DOI] [PubMed] [Google Scholar]
  • 4.Crowley SD, Coffman TM. Recent advances involving the renin-angiotensin system. Exp Cell Res. 2012;318:1049–1056. doi: 10.1016/j.yexcr.2012.02.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Bonde MM, Olsen KB, Erikstrup N, et al. The angiotensin II type 1 receptor antagonist losartan binds and activates bradykinin b2 receptor signaling. Regul Pept. 2011;167:21–25. doi: 10.1016/j.regpep.2010.11.003. [DOI] [PubMed] [Google Scholar]
  • 6.Squire IB, O’Kane KP, Anderson N, Reid JL. Bradykinin B2 receptor antagonism attenuates blood pressure response to acute angiotensin-converting enzyme inhibition in normal men. Hypertension. 2000;36:132–136. doi: 10.1161/01.hyp.36.1.132. [DOI] [PubMed] [Google Scholar]
  • 7.Gainer JV, Morrow JD, Loveland A, et al. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med. 1998;339:1285–1292. doi: 10.1056/NEJM199810293391804. [DOI] [PubMed] [Google Scholar]
  • 8.Scicli AG, Carretero OA. Renal kallikrein-kinin system. Kidney Int. 1986;29:120–130. doi: 10.1038/ki.1986.14. [DOI] [PubMed] [Google Scholar]
  • 9.Hall JM. Bradykinin receptors: pharmacological properties and biological roles. Pharmacol Ther. 1992;56:131–190. doi: 10.1016/0163-7258(92)90016-s. [DOI] [PubMed] [Google Scholar]
  • 10.Hall JM. Bradykinin receptors. Gen Pharmacol. 1997;28:1–6. doi: 10.1016/s0306-3623(96)00174-7. [DOI] [PubMed] [Google Scholar]
  • 11.Ma JX, Wang DZ, Chao L, Chao J. Cloning, sequence analysis and expression of the gene encoding the mouse bradykinin B2 receptor. Gene. 1994;149:283–288. [PubMed] [Google Scholar]
  • 12.Regoli D, Plante GE, Gobeil F., Jr Impact of kinins in the treatment of cardiovascular diseases. Pharmacol Ther. 2012;135:94–111. doi: 10.1016/j.pharmthera.2012.04.002. [DOI] [PubMed] [Google Scholar]
  • 13.Kakoki M, McGarrah RW, Kim HS, Smithies O. Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury. Proc Natl Acad Sci USA. 2007;104:7576–7581. doi: 10.1073/pnas.0701617104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Kakoki M, Smities O. The kallikrein-kinin system in health and in diseases of the kidney. Kidney Int. 2009;75:1019–1030. doi: 10.1038/ki.2008.647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Majima M, Yoshida O, Mihara H, et al. High sensitivity to salt in kininogen-deficient brown norway katholiek rats. Hypertension. 1993;22:705–714. doi: 10.1161/01.hyp.22.5.705. [DOI] [PubMed] [Google Scholar]
  • 16.Madeddu P, Vio CP, Straino S, et al. Renal phenotype of low kallikrein rats. Kidney Int. 2001;59:2233–2242. doi: 10.1046/j.1523-1755.2001.00738.x. [DOI] [PubMed] [Google Scholar]
  • 17.Alfie ME, Yang XP, Hess F, Carretero OA. Salt-sensitive hypertension in bradykinin B2 receptor knockout mice. Biochem Biophys Res Commun. 1996;224:625–630. doi: 10.1006/bbrc.1996.1076. [DOI] [PubMed] [Google Scholar]
  • 18.Alfie ME, Sigmon DH, Pomposiello SI, Carretero OA. Effect of high salt intake in mutant mice lacking bradykinin-B2 receptors. Hypertension. 1997;29(1 Pt 2):483–487. doi: 10.1161/01.hyp.29.1.483. [DOI] [PubMed] [Google Scholar]
  • 19.Ferri C, Bellini C, Carlomagno A, et al. Urinary kallikrein and salt sensitivity in essential hypertensive males. Kidney Int. 1994;46:780–788. doi: 10.1038/ki.1994.333. [DOI] [PubMed] [Google Scholar]
  • 20.Dhamrait SS, Payne JR, Li P, et al. Variation in bradykinin receptor genes increases the cardiovascular risk associated with hypertension. Eur Heart J. 2003;24:1672–1680. doi: 10.1016/s0195-668x(03)00441-x. [DOI] [PubMed] [Google Scholar]
  • 21.Wang J, Xiong W, Yang Z, et al. Human tissue kallikrein induces hypotension in transgenic mice. Hypertension. 1994;23:236–243. doi: 10.1161/01.hyp.23.2.236. [DOI] [PubMed] [Google Scholar]
  • 22.Wang DZ, Chao L, Chao J. Hypotension in transgenic mice overexpressing human bradykinin B2 receptor. Hypertension. 1997;29(1 Pt 2):488–493. doi: 10.1161/01.hyp.29.1.488. [DOI] [PubMed] [Google Scholar]
  • 23.Mukai H, Fitzgibbon WR, Bozeman G, et al. Bradykinin B2 receptor antagonist increases chloride and water absorption in rat medullary collecting duct. Am J Physiol. 1996;271(2t2):R352–R360. doi: 10.1152/ajpregu.1996.271.2.R352. [DOI] [PubMed] [Google Scholar]
  • 24.Sivritas SH, Ploth DW, Fitzgibbon WR. Blockade of renal medullary bradykinin B2 receptors increases tubular sodium reabsorption in rats fed a normal-salt diet. Am J Physiol Renal Physiol. 2008;295:F811–F817. doi: 10.1152/ajprenal.90225.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Siragy HM, Ibrahim MM, Jaffa AA, et al. Rat renal interstitial bradykinin, prostaglandin e2, and cyclic guanosine 3′,5′-monophosphate. Effects of altered sodium intake. Hypertension. 1994;23:1068–1070. doi: 10.1161/01.hyp.23.6.1068. 6t2. [DOI] [PubMed] [Google Scholar]
  • 26.Campbell DJ, Krum H, Esler MD. Losartan increases bradykinin levels in hypertensive humans. Circulation. 2005;111:315–320. doi: 10.1161/01.CIR.0000153269.07762.3B. [DOI] [PubMed] [Google Scholar]
  • 27.Blaukat A. Structure and signalling pathways of kinin receptors. Andrologia. 2003;35:17–23. doi: 10.1046/j.1439-0272.2003.00533.x. [DOI] [PubMed] [Google Scholar]
  • 28.Regoli D, Gobeil F. Pharmacology of kinin receptors: recent developments. Can J Physiol Pharmacol. 1995;73:791–796. doi: 10.1139/y95-107. [DOI] [PubMed] [Google Scholar]
  • 29.Madeddu P, Varoni MV, Demontis MP, et al. Kallikrein-kinin system and blood pressure sensitivity to salt. Hypertension. 1997;29(1 Pt 2):471–477. doi: 10.1161/01.hyp.29.1.471. [DOI] [PubMed] [Google Scholar]
  • 30.Hettinger U, Lukasova M, Lewicka S, Hilgenfeldt U. Regulatory effects of salt diet on renal renin-angiotensin-aldosterone, and kallikrein-kinin systems. Int Immunopharmacol. 2002;2:1975–1980. doi: 10.1016/s1567-5769(02)00163-7. [DOI] [PubMed] [Google Scholar]
  • 31. Staruschenko A. Regulation of transport in the connecting tubule and cortical collecting duct. Compr Physiol. 2012;2:1541–1584. doi: 10.1002/cphy.c110052. This is a comprehensive up-to-date review of molecular mechanisms govering water–electrolyte transport in the distal parts of nephron.
  • 32.Hummler E. Epithelial sodium channel, salt intake, and hypertension. Curr Hypertens Rep. 2003;5:11–18. doi: 10.1007/s11906-003-0005-1. [DOI] [PubMed] [Google Scholar]
  • 33.Schild L, Kellenberger S. Structure function relationships of ENaC and its role in sodium handling. Adv Exp Med Biol. 2001;502:305–314. doi: 10.1007/978-1-4757-3401-0_20. [DOI] [PubMed] [Google Scholar]
  • 34.Masilamani S, Kim GH, Mitchell C, et al. Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney. J Clin Invest. 1999;104:R19–R23. doi: 10.1172/JCI7840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Mamenko M, Zaika O, Ilatovskaya DV, et al. Angiotensin II increases activity of the epithelial Na+ channel (ENaC) in distal nephron additively to aldosterone. J Biol Chem. 2012;287:660–671. doi: 10.1074/jbc.M111.298919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Hansson JH, Schild L, Lu Y, et al. A de novo missense mutation of the beta subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity. Proc Natl Acad Sci U S A. 1995;92:11495–11499. doi: 10.1073/pnas.92.25.11495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Hansson JH, Nelson-Williams C, Suzuki H, et al. Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of liddle syndrome. Nat Genet. 1995;11:76–82. doi: 10.1038/ng0995-76. [DOI] [PubMed] [Google Scholar]
  • 38.Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001;104:545–556. doi: 10.1016/s0092-8674(01)00241-0. [DOI] [PubMed] [Google Scholar]
  • 39.Schild L. The ENaC channel as the primary determinant of two human diseases: Liddle syndrome and pseudohypoaldosteronism. Nephrologie. 1996;17:395–400. [PubMed] [Google Scholar]
  • 40.Schild L. The epithelial sodium channel: from molecule to disease. Rev Physiol Biochem Pharmacol. 2004;151:93–107. doi: 10.1007/s10254-004-0023-7. [DOI] [PubMed] [Google Scholar]
  • 41.Shimkets RA, Warnock DG, Bositis CM, et al. Liddle’s syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell. 1994;79:407–414. doi: 10.1016/0092-8674(94)90250-x. [DOI] [PubMed] [Google Scholar]
  • 42.Pratt JH. Central role for ENaC in development of hypertension. J Am Soc Nephrol. 2005;16:3154–3159. doi: 10.1681/ASN.2005050460. [DOI] [PubMed] [Google Scholar]
  • 43.Kakizoe Y, Kitamura K, Ko T, et al. Aberrant ENaC activation in Dahl salt-sensitive rats. J Hypertens. 2009;27:1679–1689. doi: 10.1097/HJH.0b013e32832c7d23. [DOI] [PubMed] [Google Scholar]
  • 44.Pavlov TS, Levchenko V, O’Connor PM, et al. Deficiency of renal cortical EGF increases ENaC activity and contributes to salt-sensitive hypertension. J Am Soc Nephrol. 2013;24:1053–1062. doi: 10.1681/ASN.2012080839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Mamenko M, Zaika O, Doris PA, Pochynyuk O. Salt-dependent inhibition of epithelial Na+ channel-mediated sodium reabsorption in the aldosterone-sensitive distal nephron by bradykinin. Hypertension. 2012;60:1234–1241. doi: 10.1161/HYPERTENSIONAHA.112.200469. This study defines a role of bradykinin in the regulation of ENaC activity in the distal nephron by dietary salt intake. It also suggests that the natriuretic effects of systemic ACE inhibition are caused, in part, by augmented bradykinin signaling in the distal nephron.
  • 46.Zaika O, Mamenko M, O’Neil RG, Pochynyuk O. Bradykinin acutely inhibits activity of the epithelial Na+ channel in mammalian aldosterone-sensitive distal nephron. Am J Physiol Renal Physiol. 2011;300:F1105–F1115. doi: 10.1152/ajprenal.00606.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Shen B, El-Dahr SS. Cross-talk of the renin-angiotensin and kallikrein-kinin systems. Biol Chem. 2006;387:145–150. doi: 10.1515/BC.2006.019. [DOI] [PubMed] [Google Scholar]
  • 48.Rohrwasser A, Ishigami T, Gociman B, et al. Renin and kallikrein in connecting tubule of mouse. Kidney Int. 2003;64:2155–2162. doi: 10.1046/j.1523-1755.2003.00302.x. [DOI] [PubMed] [Google Scholar]
  • 49.El-Dahr SS. Spatial expression of the kallikrein-kinin system during nephrogenesis. Histol Histopathol. 2004;19:1301–1310. doi: 10.14670/HH-19.1301. [DOI] [PubMed] [Google Scholar]
  • 50.Zeidel ML, Jabs K, Kikeri D, Silva P. Kinins inhibit conductive Na+ uptake by rabbit inner medullary collecting duct cells. Am J Physiol. 1990;258(6 Pt 2):F1584–F1591. doi: 10.1152/ajprenal.1990.258.6.F1584. [DOI] [PubMed] [Google Scholar]
  • 51.Tomita K, Pisano JJ, Knepper MA. Control of sodium and potassium transport in the cortical collecting duct of the rat. Effects of bradykinin, vasopressin, and deoxycorticosterone. J Clin Invest. 1985;76:132–136. doi: 10.1172/JCI111935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Tomita K, Pisano JJ, Burg MB, Knepper MA. Effects of vasopressin and bradykinin on anion transport by the rat cortical collecting duct. Evidence for an electroneutral sodium chloride transport pathway. J Clin Invest. 1986;77:136–141. doi: 10.1172/JCI112268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Jacques T, Picard N, Miller RL, et al. Overexpression of pendrin in intercalated cells produces chloride-sensitive hypertension. J Am Soc Nephrol. 2013;24:1104–1113. doi: 10.1681/ASN.2012080787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Pochynyuk O, Tong Q, Medina J, et al. Molecular determinants of PI(4,5)P2 and PI(3,4,5)P3 regulation of the epithelial Na+ channel. J Gen Physiol. 2007;130:399–413. doi: 10.1085/jgp.200709800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Adler S, Huang H, Loke KE, et al. Endothelial nitric oxide synthase plays an essential role in regulation of renal oxygen consumption by NO. Am J Physiol Renal Physiol. 2001;280:F838–F843. doi: 10.1152/ajprenal.2001.280.5.F838. [DOI] [PubMed] [Google Scholar]
  • 56.Bagate K, Grima M, Imbs JL, et al. Signal transduction pathways involved in kinin B2 receptor-mediated vasodilation in the rat isolated perfused kidney. Br J Pharmacol. 2001;132:1735–1742. doi: 10.1038/sj.bjp.0704027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Lal MA, Kennedy CR, Proulx PR, Hebert RL. Bradykinin-stimulated cPLA2 phosphorylation is protein kinase c dependent in rabbit CCD cells. Am J Physiol. 1997;273(6 Pt 2):F907–F915. doi: 10.1152/ajprenal.1997.273.6.F907. [DOI] [PubMed] [Google Scholar]
  • 58.Pavlov TS, Ilatovskaya DV, Levchenko V, et al. Effects of cytochrome P-450 metabolites of arachidonic acid on the epithelial sodium channel (ENaC) Am J Physiol Renal Physiol. 2011;301:F672–F681. doi: 10.1152/ajprenal.00597.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Guo LJ, Alli AA, Eaton DC, Bao HF. ENaC is regulated by natriuretic peptide receptor-dependent cGMP signaling. Am J Physiol Renal Physiol. 2013;304:F930–F937. doi: 10.1152/ajprenal.00638.2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60. Patel AB, Chao J, Palmer LG. Tissue kallikrein activation of the epithelial Na channel. Am J Physiol Renal Physiol. 2012;303:F540–F550. doi: 10.1152/ajprenal.00133.2012. This sudy suggests an alternative mechanism of ENaC regulation by the renal KKS during states with high circulating aldosterone levels.
  • 61.Picard N, Eladari D, El MS, et al. Defective ENaC processing and function in tissue kallikrein-deficient mice. J Biol Chem. 2008;283:4602–4611. doi: 10.1074/jbc.M705664200. [DOI] [PubMed] [Google Scholar]
  • 62.Silva JA, Jr, Araujo RC, Baltatu O, et al. Reduced cardiac hypertrophy and altered blood pressure control in transgenic rats with the human tissue kallikrein gene. FASEB J. 2000;14:1858–1860. doi: 10.1096/fj.99-1010fje. [DOI] [PubMed] [Google Scholar]
  • 63.Breyer MD, Breyer RM. Prostaglandin E receptors and the kidney. Am J Physiol Renal Physiol. 2000;279:F12–F23. doi: 10.1152/ajprenal.2000.279.1.F12. [DOI] [PubMed] [Google Scholar]
  • 64.Facemire CS, Nguyen M, Jania L, et al. A major role for the EP4 receptor in regulation of renin. Am J Physiol Renal Physiol. 2011;301:F1035–F1041. doi: 10.1152/ajprenal.00054.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65. Gu D, Zhao Q, Kelly TN, et al. The role of the kallikrein-kinin system genes in the salt sensitivity of blood pressure: the gensalt study. Am J Epidem. 2012;176(Suppl 7):S72–S80. doi: 10.1093/aje/kws277. This epidemiological GenSalt study demonstrates that genetic variants of the bradykinin receptor B2 gene show significant associations with salt-sensitivity phenotypes in a large and homogeneous sample of Han Chinese families.
  • 66.Madeddu P, Emanueli C, Gaspa L, et al. Role of the bradykinin B2 receptor in the maturation of blood pressure phenotype: Lesson from transgenic and knockout mice. Immunopharmacology. 1999;44:9–13. doi: 10.1016/s0162-3109(99)00105-8. [DOI] [PubMed] [Google Scholar]
  • 67.Trabold F, Pons S, Hagege AA, et al. Cardiovascular phenotypes of kinin B2 receptor- and tissue kallikrein-deficient mice. Hypertension. 2002;40:90–95. doi: 10.1161/01.hyp.0000021747.43346.95. [DOI] [PubMed] [Google Scholar]
  • 68.Saitoh S, Scicli AG, Peterson E, Carretero OA. Effect of inhibiting renal kallikrein on prostaglandin E2, water, and sodium excretion. Hypertension. 1995;25:1008–1013. doi: 10.1161/01.hyp.25.5.1008. [DOI] [PubMed] [Google Scholar]
  • 69.Emanueli C, Fink E, Milia AF, et al. Enhanced blood pressure sensitivity to deoxycorticosterone in mice with disruption of bradykinin b2 receptor gene. Hypertension. 1998;31:1278–1283. doi: 10.1161/01.hyp.31.6.1278. [DOI] [PubMed] [Google Scholar]
  • 70.Madeddu P, Anania V, Parpaglia PP, et al. Chronic kinin receptor blockade induces hypertension in deoxycorticosterone-treated rats. Br J Pharmacol. 1993;108:651–657. doi: 10.1111/j.1476-5381.1993.tb12856.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71. Waeckel L, Potier L, Chollet C, et al. Antihypertensive role of tissue kallikrein in hyperaldosteronism in the mouse. Endocrinology. 2012;153:3886–3896. doi: 10.1210/en.2012-1225. This study shows that tissue kallikrein deficiency exacerbates aldosterone–salt-induced hypertension due to, at least partially, enhanced sodium reabsorption in the distal nephron aggravating sodium retention.
  • 72.Tschope C, Schultheiss HP, Walther T. Multiple interactions between the renin-angiotensin and the kallikrein-kinin systems: Role of ace inhibition and AT1 receptor blockade. J Cardiovasc Pharmacol. 2002;39:478–487. doi: 10.1097/00005344-200204000-00003. [DOI] [PubMed] [Google Scholar]
  • 73.Casarini DE, Boim MA, Stella RC, et al. Angiotensin I-converting enzyme activity in tubular fluid along the rat nephron. Am J Physiol. 1997;272(3 Pt 2):F405–F409. doi: 10.1152/ajprenal.1997.272.3.F405. [DOI] [PubMed] [Google Scholar]
  • 74.Redublo Quinto BM, Camargo de Andrade MC, Ronchi FA, et al. Expression of angiotensin I-converting enzymes and bradykinin B2 receptors in mouse inner medullary-collecting duct cells. Int Immunopharmacol. 2008;8:254–260. doi: 10.1016/j.intimp.2007.09.013. [DOI] [PubMed] [Google Scholar]
  • 75.Sabatini RA, Guimaraes PB, Fernandes L, et al. ACE activity is modulated by kinin B2 receptor. Hypertension. 2008;51:689–695. doi: 10.1161/HYPERTENSIONAHA.107.091181. [DOI] [PubMed] [Google Scholar]
  • 76.Erdos EG, Tan F, Skidgel RA. Angiotensin I-converting enzyme inhibitors are allosteric enhancers of kinin B1 and B2 receptor function. Hypertension. 2010;55:214–220. doi: 10.1161/HYPERTENSIONAHA.109.144600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Rohrwasser A, Morgan T, Dillon HF, et al. Elements of a paracrine tubular renin-angiotensin system along the entire nephron. Hypertension. 1999;34:1265–1274. doi: 10.1161/01.hyp.34.6.1265. [DOI] [PubMed] [Google Scholar]
  • 78.Navar LG, Prieto MC, Satou R, Kobori H. Intrarenal angiotensin II and its contribution to the genesis of chronic hypertension. Curr Opin Pharmacol. 2011;11:180–186. doi: 10.1016/j.coph.2011.01.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Siragy HM, Carey RM. Role of the intrarenal renin-angiotensin-aldosterone system in chronic kidney disease. Am J Nephrol. 2010;31:541–550. doi: 10.1159/000313363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Komlosi P, Fuson AL, Fintha A, et al. Angiotensin i conversion to angiotensin II stimulates cortical collecting duct sodium transport. Hypertension. 2003;42:195–199. doi: 10.1161/01.HYP.0000081221.36703.01. [DOI] [PubMed] [Google Scholar]
  • 81.Navar LG, Kobori H, Prieto MC, Gonzalez-Villalobos RA. Intratubular renin-angiotensin system in hypertension. Hypertension. 2011;57:355–362. doi: 10.1161/HYPERTENSIONAHA.110.163519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Toma I, Kang JJ, Sipos A, et al. Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney. J Clin Invest. 2008;118:2526–2534. doi: 10.1172/JCI33293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Navar LG, Lewis L, Hymel A, et al. Tubular fluid concentrations and kidney contents of angiotensins I and II in anesthetized rats. J Am Soc Nephrol. 1994;5:1153–1158. doi: 10.1681/ASN.V541153. [DOI] [PubMed] [Google Scholar]
  • 84.Siragy HM, Howell NL, Ragsdale NV, Carey RM. Renal interstitial fluid angiotensin. Modulation by anesthesia, epinephrine, sodium depletion, and renin inhibition. Hypertension. 1995;25:1021–1024. doi: 10.1161/01.hyp.25.5.1021. [DOI] [PubMed] [Google Scholar]
  • 85. Gonzalez-Villalobos RA, Janjoulia T, Fletcher NK, et al. The absence of intrarenal ACE protects against hypertension. J Clin Invest. 2013;123:2011–2023. doi: 10.1172/JCI65460. This study shows that the absence of kidney ACE substantially blunts Ang II-dependent hypertension.
  • 86.Shen B, Harrison-Bernard LM, Fuller AJ, et al. The bradykinin B2 receptor gene is a target of angiotensin II type 1 receptor signaling. J Am Soc Nephrol. 2007;18:1140–1149. doi: 10.1681/ASN.2006101127. [DOI] [PubMed] [Google Scholar]

RESOURCES