The critical role of ion channels in kidney disease: perspective from AKI and CKD

Abstract

Ion channels, particularly those in the transient receptor potential (TRP) family, play key roles in cellular stress responses like inflammation and apoptosis, significantly impacting renal disease progression. Some channels such as TRPV1, TRPM2, TRPC6 impact renal pathology by mediating detrimental calcium influx, exacerbating oxidative stress, and promoting inflammatory pathways. Their activities are especially pronounced in conditions like ischemia and nephrotoxicity, common in acute kidney injury, and persist into chronic kidney injury, influencing fibrosis and nephron loss. Additionally, potassium and sodium channels like Kir4.1, KATP, and ENaC play critical roles in maintaining electrolyte balance and cellular energy under stress conditions. Further exploration of ion channel functionality and regulation is necessary to clarify their roles in renal disease. This review summarizes the involvement of ion channels in AKI and CKD and examines their potential clinical value in diagnosing and treating kidney disease.

1. Introduction

Kidney diseases, including Acute Kidney Injury (AKI), Acute Kidney Disease (AKD), and Chronic Kidney Disease (CKD), which are a spectrum of conditions that impair kidney function over varying time scales and complexities [1]. Annually, AKI affects approximately 13.3 million individuals globally, with about 20% of these cases developing in hospitalized patients, potentially progressing to CKD or necessitating kidney replacement therapy [2–6]. AKI is categorized into three types based on its etiology: prerenal, intrinsic renal, and postrenal. Prerenal AKI, making up about 60% of cases, is caused by inadequate blood flow to the kidneys due to conditions like fluid loss or heart failure, with treatment focused on restoring blood flow. Intrinsic renal AKI accounts for approximately 35% of cases and involves direct damage to kidney tissues from factors such as toxins or infections, requiring targeted interventions to address the specific cause. Postrenal AKI, the least common type at about 5%, results from obstructions in the urinary tract and is managed by removing the blockages to restore urine flow [7,8]. Furthermore, AKI often serves as a precursor to CKD, where initial kidney damage leads to progressive and irreversible renal impairment. CKD is characterized by a gradual loss of kidney function over time, marked by nephron loss and a compensatory hyperfiltration in remaining nephrons—a process that eventually exacerbates nephron demise [9–11]. CKD is categorized into several primary types based on its underlying causes, including diabetic nephropathy, hypertensive nephropathy, glomerulonephritis, and polycystic kidney disease [12,13]. Diabetic nephropathy, the most common form, results from long-term damage due to diabetes, emphasizing the need for blood sugar control. Hypertensive nephropathy occurs due to chronic high blood pressure damaging the kidneys’ blood vessels. Glomerulonephritis involves inflammation and damage to the kidney’s glomeruli, with various possible causes such as autoimmune diseases or infections, each needing specific treatments. Lastly, polycystic kidney disease, a genetic condition, leads to cyst formation in the kidneys, disrupting their function [12,14].

Ion channels are transmembrane proteins that help establish and control voltage potentials across cell membranes by generating a gated, water-filled pore while controlling the active flow of ions between the intra- and extracellular environment. Regulation of ion channels has been implicated in a variety of diseases, including heart disease, neurological disorders, renal failure, pain perception, and blindness. The human genome contains hundreds of genes encoding pore-forming ion channels within the plasma membrane, which are broadly categorized as either voltage-gated or ligand-gated, depending on the major factors that lead to channel opening and closing [15]. In kidney physiology, Ion channels regulate fluid and electrolyte balance which is crucial for maintaining blood volume and pressure homeostasis. Disruptions in the function of key ion channels, such as the epithelial sodium channel (ENaC), the renal outer medullary potassium channel (ROMK), can lead to severe electrolyte imbalances and contribute to the pathogenesis of kidney diseases [16–18]. The TRP family of ion channels, in particular, plays a significant role in AKI by modulating calcium signaling pathways that can exacerbate cellular injury through mechanisms involving oxidative stress, inflammation, and apoptosis. These channels’ involvement in AKI and CKD is noted for their responsiveness to pathological conditions like hypoxia and oxidative stress, common in ischemic and nephrotoxic scenarios of kidney damage [19]. In this paper we reviewed the roles of ion channels in AKI and CKD. This review aims to elucidate the different roles of different ion channels in the development of acute kidney injury and chronic kidney disease, and to provide new ideas for the prevention and treatment of kidney disease.

2. Ion channel pathways in acute kidney injury

AKI involves a continuum of molecular, structural, and functional alterations within the kidney. Ischemia-reperfusion (I/R) injury, nephrotoxins, and sepsis are among the leading causes, leading to altered renal hemodynamics, tubular obstruction, and inflammatory cascades. Vasoconstriction, oxidative stress, tubule cell death, and inflammation are central to the pathogenesis of AKI. And the role of ion channels, particularly the transient receptor potential (TRP) channels, which are permeable to calcium ions, is critical in modulating renal vascular tone, cellular metabolism, and inflammatory pathways. Understanding the specific ion channels implicated in AKI could provide crucial insights into targeted therapies.

2.1. Calcium ion flux

2.1.1. TRPV1 ion channel

Transient Receptor Potential Vanilloid 1 (TRPV1) is a nonselective cation channel, and is expressed predominantly in sensory neurons and various kidney cell types, including the renal vasculature and tubular structures. In the kidneys, TRPV1 channels are found in the renal pelvis, tubules of the renal cortex and medulla, and primary afferent C-fibers. They regulate neuropeptide release in response to mechanostimulation and are involved in maintaining renal filtration function, sodium and water homeostasis, and blood pressure regulation [20].

Persistent renal vasoconstriction in AKI reduces total kidney blood flow to about 50% of normal levels, resulting in significant congestion of the outer medullary zone and relative regional hypoxia. This leads to endothelial and tubular cell injury and death, with TRPV1 dysfunction contributing to the impaired renal excretory function and hemodynamic dysregulation. Activation of TRPV1 channels can stimulate the release of potent vasodilators like substance P and calcitonin gene-related peptide (CGRP), which can increase vascular permeability and exacerbate inflammation, worsening renal injury. However, TRPV1 agonists have also been shown to prevent ischemia/reperfusion (I/R)-induced renal dysfunction, suggesting a dual role for TRPV1 in renal pathophysiology. TRPV1 agonists like resiniferatoxin can attenuate renal tumor necrosis factor-alpha (TNF-α) mRNA expression and reduce I/R-induced renal injury by mitigating neutrophil infiltration and oxidative stress [21].

TRPV1 also influences AKI pathogenesis via its interplay with the phosphatidylinositide 3-kinase (PI3K) pathway, a known mediator of acute and chronic kidney injury [22]. The interaction between TRPV1 and PI3K family members partly regulates nociception and hyperalgesia, as phosphoinositol-3,4,5-trisphosphate (PIP3) is a key regulator of various ion channels. Enhanced activation of TRPV1 and PI3K can contribute to inflammation, leading to macrophage infiltration and increased expression of inflammatory cytokines like TNF-α and interleukin-1 beta (IL-1β). During I/R injury, TRPV1 channels act as low-pressure baroreceptors in the renal pelvis, regulating neuropeptide release from primary afferent C-fibers [23]. Degeneration of TRPV1-positive nerves exacerbates salt-induced hypertension and tissue injury via macrophage-mediated renal inflammation [24]. Additionally, activation of TRPV1 can stimulate reactive oxygen species (ROS) production, contributing to cellular damage and nephrotoxicity. Increased oxidative stress results in apoptosis and necrosis, particularly in renal tubular cells [25,26].

2.1.2. TRPM7 ion channel

The transient receptor potential melastatin (TRPM) family is a subfamily of transient receptor potential (TRP) ion channels, which are evolutionarily conserved membrane-spanning proteins. TRPM channels are key cellular sensors involved in various physiological processes, such as mineral homeostasis, blood pressure regulation, cardiac rhythm, and immunity. The TRPM family comprises eight members (TRPM1–TRPM8), each with distinct functions and permeabilities. For instance, TRPM1, TRPM3, TRPM6, and TRPM7 are highly permeable to divalent cations like Ca²⁺ and Mg²⁺, while TRPM2 and TRPM8 are nonselective cation channels, and TRPM4 and TRPM5 are monovalent cation-selective channels. Three TRPM family members (TRPM2, TRPM6, and TRPM7) possess additional enzymatic protein moieties: TRPM6 and TRPM7 are fused to α-kinase domains, whereas TRPM2 is linked to an ADP-ribose-binding NUDT9 homology domain. TRPM channels are abundantly expressed in the kidneys and are recognized as key mediators in kidney cation transport, electrolyte balance, kidney tissue homeostasis, and kidney-resident immune cell activity. Mutations in TRPM genes can lead to several inherited human diseases, and preclinical studies have highlighted TRPM channels as promising therapeutic targets [27].

Among them, transient receptor potential melastatin 7 (TRPM7), which is a bifunctional membrane protein, ubiquitously expressed in various tissues, including the kidneys. It permeates both Ca²⁺ and Mg²⁺ ions and is sensitive to intracellular Mg²⁺ and ATP levels, suggesting a role in cellular energy metabolism. In severe metabolic stress conditions such as ischemia, hypoxia, or hypoglycemia, TRPM7 serves as a direct mediator of toxic divalent cation entry, contributing to oxidative stress and inflammation. In IRI, TRPM7 expression is upregulated, which has been associated with inflammation, apoptosis, and necroptosis. Increased TRPM7 activity leads to intracellular Ca²⁺ and Mg²⁺ imbalances, disrupting cellular energy production and increasing ROS production, thereby exacerbating cell death. In particular, TRPM7 activation in cultured neurons subjected to oxygen-glucose deprivation elevates intracellular Ca²⁺ levels, promoting the generation of nitric oxide (NO) and superoxide anions (O^2-), which contribute to ROS production and oxidative stress [28].

TRPM7 is also positively correlated with tissue injury markers like lactate dehydrogenase (LDH), high-mobility group box 1 (HMGB1), and caspase-3. As a channel, TRPM7 induces calcium flickering and ROS production, leading to the activation of the NLRP3 inflammasome, a crucial player in inflammatory responses. In IRI, TRPM7 contributes to renal inflammatory responses by regulating necroptosis signaling pathways and activating immune cells, such as macrophages and neutrophils. Elevated TRPM7 expression increases the secretion of proinflammatory cytokines like TNF-α and IL-6, further amplifying inflammation and renal damage. In addition to inflammation, TRPM7 plays a role in maladaptive fibrogenesis, which can lead to CKD. TRPM7 overexpression or deletion results in glomerular number reduction, renal tubular dilation, and cyst formation in proximal tubules, indicating its importance in nephrogenesis. During renal IRI, TRPM7 regulates the apoptosis and necroptosis of endothelial and tubular epithelial cells, as well as renal vasculature. By promoting maladaptive fibrosis, TRPM7 contributes to the progression of AKI to CKD [29–31].

2.1.3. TRPM6 ion channel

TRPM6 ion channels, essential for magnesium homeostasis in the kidney’s distal convoluted tubule, also play a critical role in AKI. These channels are vital for the reabsorption of magnesium and, to a lesser extent, calcium—both key for numerous cellular functions that stabilize cells and prevent damage [32,33]. In AKI scenarios, where kidney cells face ischemic or toxic stress, TRPM6’s role is particularly crucial. Disruptions in magnesium and calcium balance can exacerbate cellular injury by destabilizing vital processes and signaling pathways, thus impairing renal function further [34–36].

Moreover, TRPM6, like its related TRPM7 channel, is a nonselective cation channel highly permeable to divalent cations, including Ca²⁺ and Mg²⁺, and features an α-kinase domain that allows it to phosphorylate itself or activate substrates. This kinase activity suggests a role in cellular energy metabolism and inflammation, which are pivotal during AKI [37]. Despite TRPM7’s more established role in the pathogenesis of AKI, TRPM6’s contributions to renal pathophysiology, especially its regulation by dietary magnesium, insulin, and hormonal influences such as epidermal growth factor, are significant. These regulatory mechanisms, if disrupted during AKI, can lead to diminished TRPM6 function, undermining the kidney’s ability to manage magnesium and calcium effectively, which in turn can severely influence the progression and severity of renal injury [38–41].

2.1.4. TRPM2 ion channel

AKI involves direct damage to the renal parenchyma, specifically the renal tubular epithelial cells. The Transient Receptor Potential Melastatin 2 (TRPM2) ion channel is expressed predominantly in proximal tubular epithelial cells, where they maintain mitochondrial integrity and cellular homeostasis. Their activation is primarily driven by intracellular adenosine diphosphate-ribose (ADPR), leading to Ca²⁺ influx and subsequent downstream effects [42].

In models of cisplatin-induced AKI, it has been observed that TRPM2 deficiency exacerbates renal dysfunction, tubular injury, and apoptosis. TRPM2 knockout mice exhibit more severe mitochondrial damage in tubular cells, characterized by mitochondrial swelling, fragmentation, and loss of cristae. This oxidative stress leads to mitochondrial dysfunction, including overexpression of the fission marker DRP1 and decreased levels of the mitochondrial outer membrane protein TOM20, with an elevated release of cytochrome c into the cytoplasm, underscoring mitochondrial-mediated apoptosis.

Furthermore, TRPM2 channels regulate autophagy, a critical mechanism for clearing damaged organelles in tubular epithelial cells. In TRPM2-deficient mice, cisplatin exposure significantly impairs autophagic flux, marked by reduced LC3B-II levels and the accumulation of p62, signifying defective autophagic clearance. This impairment is linked to the overactivation of the AKT-mTOR signaling pathway, which inhibits autophagy. RNA sequencing of TRPM2-deficient kidneys revealed upregulation of this pathway post-cisplatin treatment. Pharmacological inhibition of mTOR and AKT rescued autophagic flux, reduced apoptosis, and improved mitochondrial integrity in TRPM2-deficient mice, emphasizing the role of TRPM2 in regulating mitochondrial homeostasis.

The protective role of TRPM2 in AKI is further underscored by studies using Mito-TEMPO, a mitochondrial ROS scavenger, which alleviated mitochondrial fragmentation, ROS production, and tubular injury in TRPM2-deficient mice. Therefore, TRPM2 channels protect against cisplatin-induced AKI by regulating the Ca²⁺-AKT-mTOR signaling pathway and promoting autophagy, crucial for maintaining mitochondrial integrity and cellular survival [43–46].

2.1.5. TRPC6 ion channel

Transient receptor potential canonical 6 (TRPC6), a nonselective cation channel that mediates the influx of Ca²⁺ and other monovalent cations, also play a significant role in AKI, particularly through its effects on podocyte integrity within the kidney. As a member of the TRPC3/6/7 subgroup of the TRP family, TRPC6 is gated by diacylglycerol analogs and forms functional channels by co-assembling with other TRPC subunits, crucially maintaining the glomerular filtration barrier through interactions with proteins such as nephrin, podocin, CD2-associated protein, and α-actinin-4. These interactions are vital for podocyte function, and dysfunction in TRPC6 is linked to both familial and acquired forms of proteinuric kidney diseases, including conditions characterized by significant podocyte injury and renal fibrosis [47,48].

In the context of renal AKI, particularly IRI, TRPC6 channels are activated in response to oxidative stress and inflammation, with reactive oxygen species (ROS) generated by NADPH oxidases enhancing TRPC6 activity. This upregulation of TRPC6 has been associated with increased podocyte injury and death, as well as glomerulosclerosis, notably in doxorubicin-induced nephropathy. Beyond its role in podocyte dysfunction, TRPC6-mediated Ca²⁺ signaling contributes to apoptosis through the induction of multiple signaling pathways including calcineurin/NFAT, FasL/Fas, and caspase pathways, independent of ROS generation. Increased expression of TRPC6 following IRI is linked to apoptosis and necroptosis in renal tubular epithelial cells (TECs), and interventions such as microRNA-26a upregulation or TRPC6 siRNA can protect against IRI-induced cell death [49–52].

Furthermore, TRPC6’s influence extends to renal fibrosis and immune cell function; inhibition of TRPC6 reduces renal interstitial fibrosis likely via effects on fibroblast activation and transdifferentiation, and modulates immune cell calcium currents affecting processes like transendothelial migration and cytokine release. While the acute phase of AKI does not prominently involve TRPC6, its role becomes critical in the transition from AKI to CKD, where it influences fibrogenesis and excessive fibrosis formation, marking a potential therapeutic target to mitigate the progression to CKD following acute renal injury [53–57].

2.1.6. TRPV4 ion channel

The transient receptor potential vanilloid subtype 4 (TRPV4) ion channels, predominantly expressed in renal vascular SMCs, integral to renal physiology, playing a multifaceted role in the development and exacerbation of AKI, primarily through their effects on calcium signaling [58,59]. These effects are pronounced in various cell types within the kidney, including GECs and SMCs [60].

In the setting of AKI, especially during conditions such as sepsis and IRI, TRPV4’s role becomes critically prominent. Sepsis-associated AKI, for instance, sees a marked activation of TRPV4 in GECs. This activation facilitates an increased influx of calcium ions into the cells. Elevated intracellular calcium levels are well-known triggers for a cascade of intracellular signaling pathways, including the activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and IRF-3 (interferon regulatory factor 3). These pathways play crucial roles in the regulation of inflammatory responses and can lead to significant cellular and tissue damage. The activation of NF-κB, in particular, is a key factor in promoting inflammation within the glomerular endothelium, thereby exacerbating endothelial dysfunction—a critical element in the progression of AKI [61–64].

Moreover, the scenario of IRI reveals an increase in TRPV4 expression specifically in resistance-sized renal vessels, which are critical in regulating renal blood flow. This upregulation leads to TRPV4-mediated vasoconstriction, a response that while being a physiological attempt to control blood flow, can inadvertently contribute to microvascular dysregulation. Such dysregulation often results in outer medullary congestion, an accumulation that impairs proper blood flow and oxygen delivery to the renal tissues. The consequent hypoxia then intensifies tissue damage, not just through necrotic cell death but also through apoptosis and ferroptosis—iron-dependent forms of cell death associated with severe oxidative stress.

These processes underscore a critical aspect of TRPV4’s role: its dual influence on both hemodynamic regulation and inflammatory processes within the kidney. On one hand, TRPV4 contributes to microvascular control, influencing blood flow and vascular tone through its actions in SMCs. On the other, it affects inflammatory pathways within endothelial cells, linking mechanical and osmotic stresses to cellular immune responses. The dual impact of TRPV4 in these areas suggests that its activity during AKI is not just a response to cellular stress but a contributing factor to the progression of kidney damage [65–67] (Figure 1).

Figure 1.

The signaling pathways and their impact on physiology and pathophysiology of AKI ① activation of TRPC6 by angiotensin II leads to calcium influx, triggering NF-κB signaling, which promotes inflammation and podocyte damage, contributing to kidney fibrosis and injury. ② TRPV4 activation increases calcium levels, driving inflammatory responses via NF-κB and IRF3, exacerbating endothelial dysfunction and renal injury during conditions like sepsis and ischemia-reperfusion injury. ③ TRPV1 channels modulate the PI3K pathway, influencing inflammation, oxidative stress, and apoptosis, with dual effects on renal protection or injury, depending on the context of ischemic stress. ④ TRPM6/TRPM7 regulate magnesium and calcium homeostasis, activating the PI3K-AKT pathway to balance autophagy and inflammation, affecting cell survival during renal stress. ⑤ TRPM2 controls autophagy and apoptosis through the AKT-mTOR pathway, helping protect renal cells from mitochondrial dysfunction and oxidative damage during kidney injury.

2.2. Potassium ion flux

2.2.1. Kir4.1 channels

Kir4.1 channels, predominantly expressed in the basolateral membranes of renal distal tubules and collecting ducts, are pivotal in managing potassium homeostasis and maintaining electrochemical gradients essential for renal function. In AKI, which directly impacts kidney tissues including tubules, glomeruli, and the interstitium, Kir4.1 channels play a vital role in preserving cellular integrity under stress conditions such as hypoxia, toxins, or ischemia-reperfusion injury. The ability of these channels to regulate potassium efflux is crucial for stabilizing the membrane potential, thereby safeguarding the survival and normal function of renal cells during episodes of AKI [68,69]. Additionally, Kir4.1 channels’ responsiveness to changes in intracellular pH allows them to adjust their activity dynamically, helping to counteract disruptions in metabolic processes that often lead to acidosis within renal cells during AKI. This pH-modulating capability is essential in mitigating the adverse effects of acid buildup, which can further exacerbate cellular damage during renal injury [70,71].

Moreover, the functionality of Kir4.1 in maintaining ionic balance aids in preventing cell swelling or rupture, significantly enhancing the renal cells’ capacity to withstand osmotic and oxidative stress encountered during AKI. Although Kir4.1 channels do not directly influence renal blood flow, their role in ensuring the health of tubular cells indirectly supports the kidney’s ability to respond to vasoactive substances and maintain effective microcirculation. This overarching impact of Kir4.1 channels in managing these physiological parameters not only underscores their importance in sustaining cell survival during AKI but also highlights their crucial role in aiding the recovery and normalization of kidney function post-injury [72,73].

2.2.2. KATP channels

In the context of intrinsic or nephrogenic AKI, where direct renal tissue damage occurs due to causes like ischemia-reperfusion, toxins, or severe infection, K_ATP channels again play a protective role, but their involvement is more directly linked to mitochondrial protection. During ischemia, the opening of mitochondrial K_ATP channels helps to buffer the cells against the sudden changes in oxygen and nutrient supply. This action minimizes the production of reactive oxygen species (ROS) and reduces oxidative stress, a major contributor to cellular injury during reperfusion. By regulating the mitochondrial response to ischemia, these channels decrease the risk of mitochondrial dysfunction, which is pivotal in sustaining cell viability and function during and after ischemic episodes [74–76].

Moreover, the activity of K_ATP channels in the renal tubular cells facilitates the management of potassium and sodium homeostasis, crucial during the repair and recovery phases of AKI. By regulating the reabsorption of these ions, the channels indirectly influence the overall renal function, affecting fluid balance, electrolyte levels, and acid-base status, which are often disrupted in AKI [77,78].

2.2.3. KCa3.1 channels

For renal AKI, often a result of direct renal tissue damage from ischemia or nephrotoxins, the KCa3.1 channels have a more defined role. The literature notes that blockade of KCa3.1 channels significantly protects against nephrotoxic agents like cisplatin, which is known to induce severe AKI. This protection is primarily due to the reduction in apoptosis facilitated by these channels. In the context of cisplatin-induced AKI, KCa3.1 channels are implicated in the apoptotic pathways, particularly those involving the endoplasmic reticulum stress and the mitochondrial apoptotic pathway. Blockade of these channels inhibits the release of cytochrome c and the activation of caspases, which are critical steps in the apoptosis cascade. By reducing apoptosis, KCa3.1 channel blockade decreases tubular cell death and preserves renal function [79,80].

2.3. ASICs ion channels

In the context of AKI, which directly involves tissue damage due to factors like ischemia, toxins, or severe infections, ASIC1a channels, which is a member of Acid-sensing ion channels (ASICs), are activated by the acidic microenvironment commonly observed in ischemic tissues. This activation leads to increased calcium influx into cells, a critical pathway inducing apoptosis and further cellular damage within the kidney. Studies also indicate that inhibition of ASIC1a can reduce ischemia-reperfusion induced apoptosis in kidney cells [81,82].

3. Ion channel pathways in chronic kidney disease

AKI and CKD involve prolonged dysregulation of ion channels, which exacerbates cellular damage and fosters chronic renal dysfunction. Key ion channels such as TRPM2 and TRPV4, initially protective during AKI, may perpetuate calcium imbalances, contributing to ongoing inflammation and fibrosis characteristic of CKD. Similarly, sustained activation of sodium and potassium channels disrupts electrolyte balance, promoting hypertension and vascular resistance that aggravate renal damage. Addressing these ion channel disturbances during the AKI to CKD progression could offer therapeutic avenues to halt the evolution of chronic kidney disease (Figure 2).

Figure 2.

The pathophysiological mechanisms of AKI progressing to CKD ① stromal cells differentiate into myofibroblasts, driving excessive extracellular matrix deposition and fibrosis. ② macrophages and neutrophils release IL-6 and TNF-α, promoting persistent inflammation and tissue damage. ③ hypoxia disrupts mitochondrial function, increasing oxidative stress and contributing to cell injury. ④ G2/M arrest inhibits cellular repair, exacerbating maladaptive responses and CKD progression.

3.1. TRPV1 ion channel

TRPV1 is recognized for its role in sensory neurons, where it functions as a pain receptor responding to heat and pain stimuli. However, its expression in non-neuronal tissues, including the kidney, suggests a broader physiological role. The activation of TRPV1 in renal tissues has been shown to modulate renal hemodynamics, enhancing natriuresis and diuresis, potentially through mechanisms involving changes in renal perfusion pressure and GFR. In diabetic conditions, where CKD commonly develops as a complication, some studies observed that capsaicin administration led to significant changes in diuresis and specific renal injury markers. Notably, the chronic administration of capsaicin influenced the levels of urinary epidermal growth factor (EGF) and neutrophil gelatinase-associated lipocalin (NAG-L), both of which are considered early indicators of renal injury. The reduction in EGF levels by capsaicin treatment, significant in non-diabetic controls, suggests that TRPV1 activation may interfere with protective mechanisms against kidney damage. Conversely, the observed trends in NAG-L, a marker for tubular injury, point to a potential protective role of TRPV1 activation in diabetic kidney disease [83,84]. The dual role of TRPV1 in promoting diuresis and influencing biomarkers related to renal injury underscores the complexity of its involvement in renal pathophysiology.

3.2. TRPM7 ion channel

TRPM7 plays a critical role in magnesium homeostasis, and its functionality extends to calcium handling and cellular signaling, influencing cell survival and proliferation. In the context of CKD, vascular calcification is a common and severe complication, contributing to the morbidity and mortality associated with the disease. This process is exacerbated by disturbances in mineral metabolism, where phosphate levels often increase, promoting VSMC transdifferentiation into osteoblast-like cells that deposit calcium phosphate as hydroxyapatite, thus stiffening the vasculature and leading to cardiovascular complications. TRPM7’s role in this process is multifaceted. As magnesium is crucial for preventing inappropriate calcification, TRPM7’s ability to regulate intracellular and extracellular magnesium concentrations directly impacts vascular calcification. Studies suggest that modulation of TRPM7 activity can influence the deposition of calcium phosphate. For instance, the inhibition of TRPM7 in vascular smooth muscle cells has been shown to reduce the calcification process, implicating this channel in the pathological calcifications observed in CKD [85,86].

Further, TRPM7 interacts with several signaling pathways that govern cell phenotype and survival. Its regulation of magnesium and calcium ions supports cellular functions under physiological conditions but may contribute to pathological processes when dysregulated. In CKD, where magnesium levels may be deranged, the normal functioning of TRPM7 is crucial for preventing the maladaptive responses of VSMCs to the uremic environment, characterized by high phosphate and altered calcium signaling [87,88].

3.3. TRPM6 ion channel

TRPM6 ion channels are essential for regulating magnesium homeostasis in the kidney, particularly in the distal convoluted tubule (DCT), where they enable transcellular magnesium reabsorption. The role of TRPM6 in CKD is critical, as disruptions in magnesium balance, a common complication in CKD, can exacerbate the disease’s progression and contribute to its associated morbidity [89].

In CKD, the damage to kidney structures impairs the normal function of TRPM6, leading to magnesium wasting. This impairment is often aggravated by comorbid conditions such as diabetes and hypertension, which independently affect renal magnesium handling. Furthermore, the chronic inflammatory state associated with CKD negatively impacts TRPM6 through cytokine-mediated downregulation, reducing the kidney’s ability to compensate for low magnesium levels by upregulating TRPM6 expression and activity. Moreover, TRPM6’s functionality is intertwined with the broader dysregulation of mineral metabolism seen in CKD, including disturbances in calcium and phosphate balance. The altered hormonal environment in CKD, characterized by changes in vitamin D and parathyroid hormone levels, also influences TRPM6 activity [90–92].

3.4. TRPM2 ion channel

TRPM2, a calcium-permeable channel that is highly responsive to oxidative stress, modulates various cellular processes essential for kidney function and injury response. In studies of kidney injury, particularly under conditions such as unilateral ureteral obstruction (UUO), TRPM2 expression has been observed to increase in kidney tissues, indicating its involvement in the disease process. This upregulation appears to exacerbate the renal damage primarily through mechanisms that enhance oxidative stress, inflammation, and fibrosis [93].

Oxidative stress, a significant contributor to CKD, activates TRPM2 leading to an influx of calcium ions [94]. This influx can exacerbate cellular damage in kidney tissues by promoting apoptosis and necrosis through mechanisms that involve the activation of pro-apoptotic pathways like caspase activation. Moreover, the increased intracellular calcium can further enhance the production of reactive oxygen species (ROS), creating a damaging feedback loop that perpetuates kidney injury [42].

In the context of renal fibrosis, TRPM2’s activation influences key fibrotic pathways. For example, it has been shown that TRPM2 can regulate the activity of Transforming Growth Factor Beta 1 (TGF-β1), a critical mediator of fibrosis. By modulating this pathway, TRPM2 affects the deposition of fibrotic tissue in the kidneys, contributing to the progression of CKD. Specifically, the activation of TGF-β1-regulated pathways like the JNK signaling pathway by TRPM2 contributes to the transcription of fibrotic genes, which encode for extracellular matrix proteins and fibroblast activation markers such as α-SMA and collagen. Further complicating its role, TRPM2 activation also exacerbates inflammatory responses in kidney tissues. It enhances the NF-κB signaling, a pivotal pathway in the inflammatory response, leading to the upregulation of inflammatory cytokines such as TNF-alpha, IL-6, and MCP-1. These cytokines recruit and activate immune cells, worsening renal inflammation and injury [95,96].

3.5. TRPC6 ion channel

Transient receptor potential canonical 6 (TRPC6) ion channels affect the podocytes within kidney glomeruli, indicating TRPC6 are mediators in the pathophysiology of CKD [97]. These channels facilitate essential calcium signaling that, when dysregulated, can lead to severe kidney pathology. TRPC6 channels are vital for the normal function of podocytes, specialized cells critical for the filtration barrier in kidneys. They regulate calcium influx necessary for maintaining podocyte structure and function. However, pathological overactivation of TRPC6, often due to genetic mutations, leads to excessive calcium signaling. This dysregulation causes structural damage to podocytes, such as foot process effacement—a key feature of podocyte injury that leads to proteinuria and glomerulosclerosis. The relationship between TRPC6 activity and podocyte health underscores the sensitivity of kidney function to calcium homeostasis, emphasizing the importance of precise control over TRPC6-mediated calcium entry in maintaining the integrity of the glomerular filtration barrier [98,99].

In conditions like diabetes mellitus, where high glucose levels prevail, TRPC6 channels become overly active, exacerbating kidney damage. High glucose environments stimulate TRPC6, increasing intracellular calcium, which activates signaling pathways that promote inflammation and cellular stress. Additionally, angiotensin II, a regulator of blood pressure and fluid balance, further activates TRPC6 in diabetic nephropathy, contributing to a vicious cycle of inflammation, podocyte damage, and proteinuria. This highlights the dual impact of metabolic and hormonal factors in CKD progression through TRPC6 channels, suggesting that interventions aimed at controlling glucose levels and angiotensin II activity could mitigate TRPC6-induced podocyte damage [100,101].

Experimental models using CRISPR/Cas9 technology to inactivate TRPC6 have demonstrated protective effects against kidney damage. Rats with TRPC6 deletion exhibited reduced signs of nephrosis, such as lower levels of proteinuria, decreased glomerulosclerosis, and attenuated tubulointerstitial fibrosis compared to wild-type controls. These findings suggest that TRPC6 inactivation shields podocytes from overstimulation and subsequent injury. The reduced severity of kidney pathology in these models offers compelling evidence for the potential therapeutic value of targeting TRPC6 in the treatment of CKD, particularly in conditions predisposed to TRPC6 hyperactivity [102]. TRPC6 channels do not operate in isolation but are part of a complex network of protein interactions involving nephrin, podocin, and others that are crucial for the structural integrity of the podocyte slit diaphragm. Disruptions in these interactions or the signaling pathways that govern them can lead to altered TRPC6 activity. For instance, mutations in podocin can change the way it interacts with TRPC6, potentially leading to abnormal channel activation and contributing to the pathogenesis of glomerular diseases. Understanding these protein interactions and their role in TRPC6 regulation opens up new possibilities for targeted interventions that could stabilize podocyte function by modulating these critical molecular interactions [103–108].The expanded role of TRPC6 in CKD highlights its significance not only as a facilitator of calcium signaling in podocytes but also as a central player in the response to metabolic and systemic challenges.

3.6. TRPV4 ion channel

In the kidneys, TRPV4 is implicated in the regulation of intracellular calcium levels, a critical factor for numerous cellular functions. When activated, TRPV4 channels facilitate calcium influx into cells, which can influence a range of signaling pathways essential for kidney cell function and survival. The study focusing on TRPV4 activation by apigenin, a flavonoid found abundantly in celery, underscores its protective role against renal fibrosis induced by hypertension, which is often exacerbated by high-salt diets in conditions such as DOCA-salt-induced hypertension. Apigenin’s activation of TRPV4 channels leads to the inhibition of the fibrogenic TGF-β1/Smad2/3 signaling pathway. This pathway is a well-established mediator of fibrosis, promoting the transformation of normal kidney cells into fibroblasts that synthesize excess extracellular matrix, thereby contributing to the fibrotic build-up that characterizes CKD. By interfering with this pathway, apigenin essentially mitigates one of the fundamental pathological processes underlying renal fibrosis. Furthermore, the beneficial effects of TRPV4 activation are not limited to the direct inhibition of fibrogenic signals. The activation also induces the AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) signaling pathways, both of which are known for their roles in metabolic regulation and anti-inflammatory responses. The engagement of these pathways further assists in curbing the TGF-β1/Smad2/3 signaling, thereby enhancing the anti-fibrotic effects mediated through TRPV4 [109].

3.7. Potassium ion flux

In CKD, the dysfunction of various potassium channels plays a critical role in the disease’s pathophysiology by influencing renal blood flow, filtration processes, and cellular ionic balance. Voltage-gated potassium channels (Kv) set the membrane potential in renal cells, affecting renal hemodynamics and contributing to hypertension-related kidney damage. Inward-rectifier potassium channels (Kir) maintain the resting membrane potential crucial for normal renal cell operation, including in the glomeruli. Disruption in Kir activity can lead to hyperfiltration, an early CKD sign. Calcium-activated potassium channels (KCa) respond to intracellular calcium changes, regulating renal blood flow through vasodilation and vasoconstriction dynamics. ATP-sensitive potassium channels (K_ATP) connect cellular metabolism to electrical activity, modulating vascular tone and protecting renal tissues under ischemic conditions. Their dysfunction can enhance susceptibility to ischemic injuries due to reduced renal blood flow and oxygenation.

K_ATP channels also stabilize the membrane potential vital for podocyte survival, critical for maintaining the glomerular filtration barrier. Dysfunction in these channels can lead to podocyte loss, impaired filtration, and proteinuria. Nicorandil, a K_ATP channel opener, protects podocytes by preserving manganese superoxide dismutase (MnSOD), reducing oxidative stress and its related damage. Beyond podocytes, nicorandil’s activation of K_ATP channels decreases oxidative stress markers like renal nitrotyrosine and urine 8-hydroxy-2′-deoxyguanosine, mitigating fibrosis and further kidney function decline. Additionally, nicorandil’s modulation of macrophage activity through the reduction of xanthine oxidase expression curbs inflammation in CKD, helping prevent tissue damage and fibrosis [110,111] (Figure 3; Table 1).

Figure 3.

The activation of TRP channels modulates key pathways involved in CKD ①TRPV1 activation regulates renal sympathetic outflow, influencing hemodynamics and contributing to diuresis and natriuresis, particularly in the context of kidney injury. ② TRPM7 controls magnesium homeostasis, regulating vascular smooth muscle cell differentiation and preventing vascular calcification, a major complication in CKD. ③ TRPM2, activated by oxidative stress, leads to calcium influx, promoting mitochondrial dysfunction, ROS production, and apoptosis, thus exacerbating kidney damage. ④ TRPV4, activated by TGF-β, facilitates calcium entry and engages the PI3K pathway, driving myofibroblast transdifferentiation, which accelerates renal fibrosis.

Table 1.

The key roles of ion channels in AKI and CKD.

Ion Channels	Ion Type	Locus of expression	Key roles in AKI	Key roles in CKD
TRPV1	Ca²⁺	renal pelvis, tubules of the renal cortex and medulla, and primary afferent C-fibers	activation of TRPV1 can reduce inflammation and oxidative stress	reduce EGF levels
TRPM7	Ca²⁺ and Mg²⁺	tubular endothelial cell	promotion of calcium inward flow exacerbates cellular damage, and its inhibition may be protective	influence the deposition of calcium phosphate
TRPM6	Ca²⁺ and Mg²⁺	distal convoluted tubule	regulate magnesium ion uptake and homeostasis; influence cellular energy metabolism and inflammation	influence mineral metabolism, including disturbances in calcium and phosphate balance
TRPM2	Ca²⁺	proximal tubular epithelial cells	maintain mitochondrial integrity and cellular homeostasis	regulate the activity of Transforming Growth Factor Beta 1 (TGF-β1)
TRPC6	Ca²⁺ and other monovalent cations	podocytes	regulation of Ca²⁺ inward flow promotes cell injury and podocyte dysfunction and inhibition of its activity may help attenuate renal injury	modulation of Ca²⁺ influx leads to podocyte injury and fibrosis
TRPV4	Ca²⁺	GECs and SMCs	dual influence on both hemodynamic regulation and inflammatory processes	TGF-β1/Smad2/3 signaling pathway; AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) signaling pathways
Kir4.1	K+	basolateral membranes of renal distal tubules and collecting ducts	preserving cellular integrity; modulate pH	unknown
KATP	K+	unknown	manage potassium, sodium homeostasis and mitochondrial homeostasis	connect cellular metabolism to electrical activity, modulate vascular tone
KCa3.1	K+	unknown	participate in apoptotic pathways	regulate the dynamics of vasodilation and vasoconstriction
ASICs	Na+	unknown	induce apoptosis and further cellular damage	unknown

4. Discussion

The comprehensive analysis of ion channel dynamics in renal pathophysiology as explored in this review underscores their multifaceted roles across the spectrum of kidney diseases, including AKI and CKD. Ion channels, due to their key roles in regulating cellular homeostasis and stress responses, are emerging as critical therapeutic targets in renal diseases. In particular, ion channels involved in calcium signaling, such as TRPV1, TRPM2, and TRPC6, have shown potential in modulating inflammation, oxidative stress, and fibrosis, which are central to the progression of both AKI and CKD. Therapeutic strategies targeting these channels aim to restore cellular balance, prevent excessive inflammatory responses, and reduce renal injury, potentially altering the course of these diseases. Molecular conduits not only orchestrate fundamental cellular processes such as ion transport, cellular signaling, and metabolic regulation but also are pivotal in disease progression and therapy. Development of AKI and CKD involves a continuum of events driven by persistent cellular damage, systemic conditions, and exacerbated by dysregulated ion channel activity, suggesting that therapeutic targeting of specific ion channels could markedly alter disease outcomes.

In the context of AKI, ion channels like TRPV1, TRPM2, and ASIC1a are critical mediators of calcium homeostasis and cellular integrity. TRPV1, for instance, plays a dual role by exacerbating renal damage through inflammation while providing vasodilatory responses that protect renal function. Similarly, TRPM2’s involvement in oxidative stress regulation and its protective role against mitochondrial damage highlight its potential as a therapeutic target. The activation of ASIC1a in the acidic environment typical of ischemic injuries underscores its role in exacerbating cellular damage through calcium overload. Targeting these channels could, therefore, provide a nuanced approach to mitigating the cellular stresses that precipitate AKI, potentially staving off progression to CKD.

As AKI may segue into CKD, the roles of ion channels like TRPC6 and TRPV4 become increasingly significant. TRPC6’s involvement in podocyte function and glomerular filtration barrier integrity directly impacts CKD progression, particularly under diabetic conditions where its dysregulation leads to exacerbated podocyte damage and proteinuria. Similarly, TRPV4’s role in regulating endothelial and tubular function under stress conditions like hypertension and its potential in fibrosis modulation through TGF-β1/Smad2/3 signaling pathways presents a therapeutic angle that could be exploited to alleviate fibrogenesis in CKD.

Furthermore, the review highlights the clinical implications of these findings, suggesting that interventions targeting specific ion channels could ameliorate the severe consequences of renal diseases. For instance, modulation of TRPV4 and TRPC6 activity offers a promising therapeutic avenue to prevent further deterioration of AKI and CKD by stabilizing renal function and preventing fibrosis, respectively. Similarly, targeting TRPM2 and ASIC1a could reduce oxidative stress and inflammation in AKI, addressing both immediate and prolonged renal injury.

Importantly, this discussion also contemplates the economic and healthcare burdens posed by renal diseases, emphasizing the need for innovative therapeutic strategies that transcend conventional treatments. By elucidating the roles of ion channels in both AKI and CKD, this review lays the groundwork for future research aimed at developing ion channel-targeted therapies, which could significantly improve patient outcomes and reduce healthcare costs. While the potential of targeting ion channels in renal disease therapy is promising, challenges remain in ensuring specificity and minimizing off-target effects. Ion channels often have widespread expression in various tissues, raising concerns about potential side effects. For example, while TRPV1 agonists may offer protective effects in AKI, their role in nociception and pain perception needs careful consideration. Furthermore, the clinical translation of ion channel modulators faces hurdles in terms of drug delivery, dosage optimization, and long-term safety. However, advancements in nanotechnology, gene therapy, and selective modulators may offer solutions to these challenges, enabling the development of targeted therapies that can alter the course of renal disease while minimizing systemic effects [112–114].

In conclusion, Both AKI and CKD are the result of a complex interaction of multiple factors in which ion channels play a crucial role. Understanding these roles not only sheds light on the pathophysiological mechanisms involved but also opens new avenues for targeted therapeutic interventions. Future research should focus on the development of more selective and effective ion channel modulators, as well as conducting clinical trials to evaluate their safety and efficacy in humans. Personalized medicine approaches could play a crucial role in determining which patients would benefit most from ion channel-targeted therapies based on the specific ion channels involved in their disease pathology. Furthermore, the integration of ion channel modulation with other therapeutic strategies, such as anti-inflammatory or antifibrotic drugs, could offer a multi-faceted approach to treating both AKI and CKD.

Glossary

Abbreviations

AKI

Acute kidney injury

CKD

chronic kidney disease

TRP

Transient Receptor Potential

GFR

glomerular filtration rate

ENaC

epithelial sodium channel

ROMK

renal outer medullary potassium channel

IRI

Ischemia-reperfusion injury

TRPV1

Transient Receptor Potential Vanilloid 1

CGRP

calcitonin gene-related peptide

TNF-α

tumor necrosisn factor-alpha

PI3K

phosphatidylinositide3-kinase

PIP3

phosphoinositol-3,4,5-trisphosphate

IL-1β

interleukin-1 beta

ROS

reactive oxygen species

TRPM

transient receptor potential melastatin

NO

nitric oxide

O^2-

superoxide anions

LDH

lactate dehydrogenase

HMGB1

high-mobility group box 1

ADPR

adenosine diphosphate-ribose

TRPC6

Transient receptor potential canonical 6

TECs

tubular epithelial cells

SMCs

smooth muscle cells

GECs

glomerular endothelial cells

NF-κB

nuclear factor kappa-light-chain-enhancer of activated B cells

IRF-3

Interferon regulatory factor 3

ASICs

Acid-sensing ion channels

GFR

glomerular filtration rate

EGF

epidermal growth factor

NAG-L

neutrophil gelatinase-associated lipocalin

VSMC

vascular smooth muscle cell

DCT

distal convoluted tubule

UUO

unilateral ureteral obstruction

TGF-β1

Transforming Growth Factor Beta 1

TRPC6

Transient receptor potential canonical 6

AMPK

AMP-activated protein kinase

SIRT1

sirtuin 1

MnSOD

manganese superoxide dismutase

Funding Statement

This study was supported by Project Sponsored by Innovative Research Team of High-Level Local Universities in Shanghai (No. SHSMU-ZDCX20212200) , the Fundamental Research Funds for the Central Universities (No. YG2023LC13), Science and Technology Commission of Shanghai Municipality (No.23430761100).

Disclosure statement

No potential conflict of interest was reported by the author(s).