TMEM16A inhibits renal tubulointerstitial fibrosis via Wnt/β-catenin signaling during hypertension nephropathy

Abstract

Background and objectiveHypertensive nephropathy is the second leading cause of end-stage renal disease, but its underlying pathogenesis remains unclear. Therefore, this study aimed to explore whether transmembrane protein 16 A (TMEM16A), the molecular basis of calcium-activated chloride channels (CaCC), is involved in the development and progression of hypertensive nephropathy. MethodsIn vivo and in vitro experiments were conducted using a hypertensive murine model and human kidney proximal tubular epithelial cells (HK-2 cells), respectively. Experimental resultsThe expression of TMEM16A was down-regulated in renal samples of hypertensive nephropathy patients and hypertensive model mice, accompanied by excessive deposition of extracellular matrix proteins (ECM) such as Fibronectin, Laminin, Collagen I and Collagen III, the up-regulation of α-smooth muscle actin (α-SMA) expression, and the decrease of E-cadherin. Overexpression of TMEM16A or knockdown of TMEM16A inhibited or promoted the expression of Wnt/β-catenin signaling pathway proteins Wnt3a, LRP5 and active β-catenin in HK-2 cells, preventing the epithelial-to-mesenchymal transition (EMT) of renal tubules, and the synthesis of ECM components. ConclusionIn angiotensin II (Ang II)-induced hypertensive nephropathy, TMEM16A was identified as a key player inhibiting the detrimental changes in renal tubules, suggesting a potential avenue for mitigating renal damage in hypertensive nephropathy.