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KCa3.1: a new player in progressive kidney disease

Huang, Chunling; Pollock, Carol A.; Chen, Xin-Ming

Current Opinion in Nephrology and Hypertension: January 2015 - Volume 24 - Issue 1 - p 61–66
doi: 10.1097/MNH.0000000000000083

Purpose of review Hypertension and hyperglycaemia are major risk factors that result in chronic kidney disease (CKD). Achievement of blood pressure goals, optimal control of blood glucose levels and the use of agents to block the renin–angiotensin–aldosterone system slow the progression of CKD. However, not all patients are benefited by these interventions and novel strategies to arrest or reverse the pathological processes inherent in CKD are needed. The therapeutic potential of targeting KCa3.1 in CKD will be discussed in this review.

Recent findings Blockade of KCa3.1 ameliorates activation of renal fibroblasts in diabetic mice by inhibiting the transforming growth factor-β1/small mothers against decapentaplegic pathway. A concomitant reduction in nuclear factor-κB activation in human proximal tubular cells under diabetic conditions has been observed. Advanced glycosylated endproducts induce both protein expression and current density of KCa3.1, which, in turn, mediates migration and proliferation of vascular smooth muscle cells via Ca2+-dependent signalling pathways.

Summary Studies have clearly demonstrated a causal role of chronic hyperglycaemia and hypertension in the development of CKD. However, a large proportion of patients develop end-stage kidney disease despite strict glycaemic control and the attainment of recommended blood pressure goals. Therefore, it is essential to identify and validate novel targets to reduce the development and progression of CKD. Recent findings demonstrate that genetic deletion or pharmacologic inhibition of KCa3.1 significantly reduces the development of diabetic nephropathy in animal models. However, the consequences of blockade of KCa3.1 in preventing and treating established diabetic nephropathy in humans warrants further study.

Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia

Correspondence to Professor Carol A. Pollock, Department of Medicine, University of Sydney, Professorial Suite, Level 7, Kolling Building, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. Tel: +61 2 9926 4652; fax: +61 2 9926 5715; e-mail:

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Chronic kidney disease (CKD) is a global health problem [1]. The progressive nature of the disease has both personal and societal impact, resulting in the need for renal replacement therapy and an increased risk of premature death from associated cardiovascular disease. ‘Best practice’ therapy includes optimal blood pressure and glycaemic control, and reduction in albuminuria. However, such strategies have only slowed the progression to end-stage kidney disease (ESKD) [2]. Hence, novel therapeutic strategies are necessary to effectively arrest or reverse progressive renal functional decline. KCa3.1 (also known as KCNN4) is increasingly recognized as a therapeutic target in diabetic renal disease and indeed in associated cardiovascular disease [3,4,5▪▪]. This article reviews the role and mechanisms of KCa3.1 in progressive diabetic CKD and its potential role as a therapeutic target.

Box 1

Box 1

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As reviewed by Jha et al.[1], CKD is defined as a reduced glomerular filtration rate, increased urinary albumin excretion or both. The prevalence is estimated to be 8–16% worldwide. CKD leads to ESKD and generally requires kidney replacement therapy such as dialysis or kidney transplantation [6]. Loss of kidney function is associated with significantly increased cardiovascular morbidity and mortality, which collectively represents a huge economic burden of healthcare and lost productivity.

It is well recognized that diabetes mellitus and hypertension are the leading causes of chronic kidney disease in all developed and many developing countries [1]. The prevalence of CKD and ESKD attributable to hypertension continues to rise worldwide. Hypertension remains a common factor complicating all forms of CKD, and is almost universally seen in diabetic nephropathy [7]. To date, the exact mechanisms of hypertensive nephropathy remain unclear. Two complementary pathogenic mechanisms have been proposed, both of which involve the vasculature [8]. Chronic hypertension leads to changes in the systemic and renal macro and microvasculature, resulting in loss of renal auto-regulation, increased glomerular capillary pressure and consequent hyperfiltration-mediated tubular injury [8]. Hyperfiltration contributes to glomerular proteinuria, which promotes the release of cytokines and growth factors by mesangial cells and downstream tubular epithelial cells [8]. In addition, hypertension induces vascular stretch, endothelial dysfunction and the consequent activation of the intra-renal renin–angiotensin system (RAS), which amplifies the release of cytokines and growth factors, recruitment of inflammatory cells, increased matrix production and finally progressive glomerular and interstitial fibrosis [8,9].

Diabetic kidney disease is a devastating complication of diabetes mellitus and the most common cause of CKD. Approximately 35–40% of all new cases require dialysis therapy throughout the world. Chronic hyperglycaemia leads to persisted metabolic and haemodynamic changes which regulate intracellular signalling pathways, transcription factors, cytokines, chemokines and growth factors, and consequently results in renal injury, and the development of CKD and renal failure [10▪,11▪,12].

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The calcium-activated potassium channels (KCa channels) have been classified into three groups. KCa3.1 belongs to the intermediate conductance channels and is gated solely by internal calcium ions [13]. By fluorescence in-situ hybridization, Ghanshani et al.[14] mapped the KCa3.1 gene to chromosome 19q13.2. The KCa3.1 protein contains six putative transmembrane domains, a conserved pore region and a leucine zipper-like motif near the C terminus [13]. The primary function of the KCa3.1 channel is to modulate Ca2+ influx during cellular activation and proliferation. KCa3.1 is widely expressed throughout the body, including in erythrocytes, platelets, T and B cells, mast cells, monocytes/macrophages, microglia, epithelial tissues, vascular endothelial cells, fibroblasts and vascular smooth muscle cells (VSMCs) [5▪▪,15–20]. In these cells, KCa3.1 regulates Ca2+ entry and modulates Ca2+ signalling. Basic fibroblast growth factor (FGF) induces significant up-regulation of KCa3.1 mRNA and protein in mouse renal tubulointerstitial fibroblasts, resulting in cell proliferation through receptor tyrosine kinase activity and the Ras/Raf/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK)-signalling cascade [21]. Recently, we have demonstrated increased expression of mRNA and protein of KCa3.1 and functional activity induced by both transforming growth factor beta (TGF-β)1 and high glucose in cultured renal proximal tubular cells and fibroblasts [3,4,22,23]. A robust up-regulation of KCa3.1 has been observed in fibrotic kidneys induced by unilateral ureteral obstruction in mice [21], in the renal proximal tubular cells of patients with diabetes mellitus and in mouse models of diabetic nephropathy [3].

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Endothelial cells, VSMCs and fibroblasts comprise the major cell types of vasculature, and dysfunction of each of these cell types contributes to hypertension. As stated above, hypertension is characterized by endothelial dysfunction [24]. The endothelium is a multifunctional organ which is critically involved in modulating vascular tone and structure. Endothelial cells produce a wide range of factors that also regulate cellular adhesion, thromboresistance, smooth muscle cell proliferation and vessel wall inflammation [25]. Thus, endothelial dysfunction leads to impairment of endothelium-dependent vasodilatation and is associated with several pathophysiological conditions, including atherosclerosis, hypertension and diabetes [25]. In these pathological conditions, endothelial cells become a source of endothelium-derived contracting factors including endothelin and angiotensin II, cyclooxygenase-derived prostanoids and superoxide anions [24]. These factors are considered responsible for impaired endothelium-dependent vasodilation in patients with essential hypertension. VSMCs are the stromal cells of the vascular wall, and are involved in all the physiological functions and the pathological changes taking place in the vascular wall. VSMCs are a key player in the regulation of blood pressure [26,27]. Stiffness of individual VSMCs has been shown to mediate reduced vascular compliance [28], and reversing arterial stiffness has been suggested as a new strategy for pharmacological treatments of hypertension [28,29]. As well reviewed [30], KCa3.1 is abundantly expressed in endothelial cells in mature and healthy vessels. However, KCa3.1 is rapidly up-regulated when smooth muscle cells undergo phenotypic modulation. KCa3.1 has been demonstrated to play a significant role in endothelial cell proliferation [31]. Physiologically, KCa3.1 maintains dilation of resistance arterioles, and thus regulating blood pressure [32,33], and the importance of endothelium-derived hyperpolarizing factor (EDHF) in controlling vascular tone and blood pressure has been well studied in vivo[34–36]. Although selective KCa3.1 activation results in lowering of blood pressure through targeting the EDHF-dilator system and the endothelium [37,38], pharmacological inhibition of KCa3.1 has not been shown to increase blood pressure in mice [39], in healthy human volunteers and patients [40].

It is well documented that growth factors up-regulate KCa3.1 largely through activation of the mitogen-activated protein kinases (MAPK) cascade. KCa3.1 signalling in VSMCs has been well reviewed [5▪▪,30]. In brief, growth factors bind to their receptors, initiating a signalling cascade in which activation protein-1 and histone acetylation, as well as the release of the repressor element 1-silencing transcription factor (REST) suppression, up-regulate KCa3.1 channels [30]. The promoter of KCa3.1 gene contains a REST binding site and the binding of the REST to the promoter suppresses the KCa3.1 transcription [41]. The fibrogenic chemokine basic FGF up-regulates KCa3.1 expression in murine renal fibroblasts via a MEK-dependent mechanism, and selective blockade of KCa3.1 potently inhibits fibroblast proliferation by inducing G(0)/G(1) arrest [21]. Basic fibroblast growth factor also increases KCa3.1 expression via the ERK pathway in both fibroblasts [18], and in human umbilical vein endothelial cells [31], which leads to increased cell proliferation. KCa3.1 up-regulation is necessary for SMC dedifferentiation, proliferation and migration, which contributes to atherosclerosis [30]. It has recently been reported that KCa3.1 plays an important role in VSMC proliferation via controlling Ca2+-dependent signalling pathways [42], and advanced glycosylated endproduct (AGE)-induced migration and proliferation of rat VSMCs are related to the up-regulation of KCa3.1 channel expression and activity. ERK1/2, P38-MAPK and phosphoinositide 3-kinase are all involved in the regulation of KCa3.1 channel expression in VSMCs [43]. Given that vascular pathology is a key component of progressive CKD [44], specifically targeting KCa3.1 may benefit hypertensive nephropathy.

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It is widely accepted that although many factors are implicated in the cellular dysfunction observed in diabetes mellitus, high glucose-induced TGF-β1 [45–49] and downstream signalling via the small mothers against decapentaplegic (Smad) or non-Smad pathways are key to the development of nephropathy [50]. Our own studies have largely focused on the role of the tubular cell in the development of diabetic nephropathy [3,51]. High glucose either directly or indirectly influences a variety of nuclear receptors, transcription factors and signal transduction cascades, which ultimately modify cytokine and chemokine production, thus inducing inflammation, extracellular matrix (ECM) accumulation and epithelial to mesenchymal transition (EMT). As alluded to above, KCa3.1 is up-regulated in ureteric obstruction-induced renal fibrosis, and selective KCa3.1 blockade with triarylmethane-34 (TRAM34), or when induced in KCa3.1−/− mice attenuates the progression of renal fibrosis [21]. This demonstrates that KCa3.1 is involved in renal fibrogenesis and suggests that KCa3.1 may represent a therapeutic target for the treatment of renal fibrosis [21].

We have recently demonstrated up-regulated KCa3.1 in the kidneys of a murine model of diabetic nephropathy and in patients with diabetic nephropathy [3]. In-vitro studies, using cultured human proximal tubular cells and whole-cell patch clamp techniques, confirm that TGF-β1 induces a large KCa3.1 K-current that is inhibited by TRAM34 [23]. We have also shown in a diabetic mouse model, the selective KCa3.1 inhibitor TRAM34 or when diabetes is developed in KCa3.1−/− mice, the TGF-β1/Smad pathway is inhibited and renal fibrosis is attenuated [3]. Molecular mechanistic studies further demonstrate that blockade of KCa3.1 attenuates diabetic renal interstitial fibrogenesis through inhibition of phosphorylation of Smad2/3 and ERK1/2, and hence a reduction in fibroblast activation [23]; inhibition of KCa3.1 suppresses TGF-β1-induced monocyte chemotactic protein (MCP)-1 expression in human proximal tubular cells through inhibition of Smad3, p38 and ERK1/2 signalling pathways [23]; and KCa3.1 blockade inhibits high glucose or hyperglycaemia-induced overexpression of the pro-inflammatory cytokine CCL20 in human proximal tubular cells and in the kidneys of diabetic mice through inhibition of the nuclear factor-κB pathway [23]. Collectively, these results suggest that KCa3.1 is a potential therapeutic target in diabetic nephropathy.

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A large amount of literature supports the tenet that up-regulation of KCa3.1 in the vasculature contributes to vascular and associated pathology [5▪▪,30,52]. We have shown in murine models of diabetes mellitus that gene silencing or pharmacological blockade of the KCa3.1, when introduced at the induction of diabetes mellitus, confers significant protection against the subsequent development of diabetic-induced interstitial fibrosis [3]. We have further demonstrated that the mechanism is in part due to inhibition of TGF-β1 signalling [3,4,22]. However, the role of KCa3.1 blockade in arresting the progression of or reversal of the functional decline and histological abnormalities in established diabetic nephropathy warrants further studies before proceeding to clinical trial. Recently, it has been reported that the KCa3.1 blocker TRAM34 blocks VSMC calcification, thus providing a rationale for further studies exploring KCa3.1 inhibition by TRAM34, or other inhibitors, in vascular calcification [53]. One study has suggested that KCa3.1 channels play an important role in the pathogenesis of chronic allograft nephropathy and therefore constitute an attractive target for the prevention of arteriopathy [54]. To date, reports demonstrated that pharmacological inhibition of KCa3.1 did not lead to significant side effects in mice [39] and in over 500 human volunteers and patients taking senicapoc for up to 2 years [40]. However, the role of KCa3.1 blockade in vasculopathy and nephropathy requires longer-term animal studies and clinical trials, with detailed studies of ‘off-target’ effects, including cardiovascular risks.

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Current treatment of CKD is directed at targeting traditional renal and cardiovascular risk factors. Glucose lowering, antihypertensive therapy and RAS blockade have been shown to slow, but not prevent the progression of diabetic nephropathy. Reports have suggested that KCa3.1 contributes to a variety of cell activation processes present in CKD, such as inflammation, fibrosis and vascular remodelling. Blockade of KCa3.1 attenuates cytokine and hyperglycaemia-induced pathological responses in fibroblasts, renal tubular cells, VSMCs and endothelial cells. The modulation of KCa3.1 in hypertensive and diabetic nephropathy is summarized in Fig. 1. Chronic hypertension leads to the up-regulation of KCa3.1 through EDHF and MAPK cascade, which mediates the activation, proliferation and migration of vascular cells, including renal endothelial cells and VSMCs. The activated renal endothelial cells and VSMCs produce large amounts of cytokines and chemokines, and attract inflammatory cell infiltration, which results in chronic inflammatory and fibrotic responses, and eventually renal fibrosis. In patients with diabetes mellitus, chronic hyperglycaemia leads to the up-regulation of KCa3.1 through TGF-β, AGEs and oxidative stress signalling pathways, which mediates renal tubular injury and activation of renal fibroblasts, and, subsequently, chronic inflammatory and fibrotic responses and renal fibrosis. Although pharmacological KCa3.1 activators lower blood pressure, KCa3.1−/− mice and pharmacological inhibitors do not lead to increased blood pressure in mice or humans. KCa3.1 blockade may be a potential therapeutic strategy in CKD as it has been shown to impact positively on the inflammation, fibrosis and vasculopathy that collectively characterize progressive CKD.



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Financial support and sponsorship

The work is supported by Juvenile Diabetes Research Foundation International (Strategic Research Agreement: 2-SRA-2014–258-Q-R) and the University of Sydney Postgraduate Award (C.H.).

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Conflicts of interest


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

  • ▪ of special interest
  • ▪▪ of outstanding interest
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chronic kidney disease; diabetic kidney disease; KCa3.1; transforming growth factor-β

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