The role of TRPC6 channel in chronic kidney disease

The canonical transient receptor potential (TRPC) family comprises nonselective ion-permeable channels that may be activated by receptor-operated channel activation or as a response to oxidative and mechanical stress. TRPC channels favor Ca²⁺ transport due to high relative permeability for two valent cations and the concentration gradient for Ca²⁺. It has been established that TRPC family members play a role in the pathogenesis of glomerular disease processes and chronic kidney disease (CKD). Among others, TRPC6 is the most studied protein and has been a significant focus for drug discovery in recent years. The first reports about the role of TRPC6 in the glomerulus and kidney function were published in 2005 (1, 2). These studies revealed that TRPC6 ion channel protein is expressed in podocytes and is an essential component of the glomerular slit diaphragm. Moreover, gain-of-function mutations in TRPC6 gene enhance intracellular Ca²⁺ signals and are directly correlated with the development of focal and segmental glomerulosclerosis. These seminal works created multiple intriguing physiological and pathophysiological questions and boosted the development of renal TRPC research for many years ahead.

Recently, the renal field has made significant progress in understanding the mechanisms by which TRPC6 causes kidney disease. The regulation of glomerular function by extracellular nucleotides leading to changes in permeation through slit diaphragms was directly linked to Ca²⁺-permeable TRPC channels. Furthermore, the critical role of TRPC6 in angiotensin II-dependent and ATP-dependent Ca²⁺ flux in glomerular podocytes and the subsequent role of these signaling pathways in the development of albuminuria have been shown (3, 4). Similarly, TRPC6-mediated modulation of intracellular Ca²⁺ was observed during the stimulation of κ-opioid receptors in podocytes (5). The accumulated evidence suggests that overactivation of the glomerular G protein-coupled receptor/TRPC6 pathway leads to loss of podocytes and aggravation of renal damage. Further studies have indicated that TRPC6 activation leads to changes in the cytoskeleton of both podocyte and mesangial cells, adding complexity in TRPC6-dependent modulation of glomerular function (6). In renal tissue, TRPC6 expression was also found beyond the glomerulus and has now been reported in the collecting duct, afferent arterioles, fibroblasts, and immune dendritic and macrophages cells (7).

Research studies have provided evidence that pharmacological inhibition of TRPC6 channels may be a helpful tool to reduce the severity of kidney disease. Consequently, TRPC6 is being extensively investigated as a target for drug discovery. There are several commercially available potent TRPC6 inhibitors and blockers (SAR 7334, GSK 2833503 A, BI-749327, SH045, and larixyl acetate); however, their selectivity may vary. The development of therapeutic agents based on specific TRPC6 inhibitors is still under development and requires evaluation in research and clinical studies. Alternatively, genetic rodent models have been used to understand TRPC6 involvement in the modulation of renal function. The Trpc6-deficient mouse was initially created by the Lutz Birnbaumer group, and podocyte-specific transgenic mice with overexpression mutant forms of Trpc6 related to human focal and segmental glomerulosclerosis (8) are commercially available from Jackson Laboratory. In many renal tissues, TRPC6 channels may coexpress and share function with other TRPC members like TRPC5 and TRPC3. This fact should be considered during the development of knockout models and selective pharmacological tools since it may result in compensatory overexpression or nonselective inhibition of the relative TRPC channel subunits.

Based on expression and function, TRPC6 channels may be implicated in podocyte pathophysiology, renal fibrosis, and tubulointerstitial disease. This fact extended the focus of TRPC6-related studies from the glomerulus to the whole kidney and identification of the TRPC6 signaling impact to the main risk factors for CKDs like diabetes and high blood pressure. The renoprotective effects of Trpc6 knockout on the progression of diabetic kidney disease have been reported in Dahl SS^Trpc6−/− rats (9); however, this study has significant limitations due to the moderate effects and observations at a later stage of the disease progression. An elegant study by Wang et al. (10), recently published in the American Journal of Physiology-Renal Physiology, revealed several important facts and further improved our understanding of the role of TRPC6 in CKD. The authors used Trpc6 knockout mice and a chronic kidney injury model of simultaneous renal exposure to hypertension and streptozotocin (STZ)-induced diabetes. A moderate dose of STZ was used to avoid rapid progression of the diabetic-related injury and STZ-related renal toxicity. Mild hypertension was induced by aortic constriction surgery, where one kidney was exposed to high blood pressure and the second kidney was used as a control. To derive high-quality data and conclusions, the authors performed advanced techniques to measure blood pressure, total and single kidney glomerular filtration rate, and renal damage in high or normal/reduced pressure kidneys from wild-type and Trpc6-knockout diabetic animals. As a result of the experiments, the authors concluded that the synergy of mild hyperglycemia and mild hypertension induces severe renal injury compared with the kidney exposed to high glucose and metabolic stress only. Moreover, Trpc6 deficiency strongly ameliorated the severity of renal dysfunction, including glomerular filtration rate and proteinuria, when diabetes and hypertension occurred together. Notably, knockout of Trpc6 reduced apoptotic injury in both glomerular and tubular cells, suggesting that Trpc6 plays an important role in the development of pathology in different nephron segments.

In conclusion, despite the wealth of information, the impact of TRPC6 deletion or pharmacological blockade in specific renal cells and the exact role of corresponding molecular pathways in the pathogenesis of kidney injury will require further investigation. Nevertheless, a vast amount of accumulated evidence suggests that modulation of TRPC6 and other TRPC family member signaling have the potential to combat the effects of CKD and concomitant pathologies.

GRANTS

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grant DK126720.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author.

AUTHOR CONTRIBUTIONS

O.P. drafted manuscript and approved final version of manuscript.