TRPM7 contributes to TGF-ß signaling in renal fibroblast

Mammalian transient receptor potential melastatin (TRPM), the non-selective cation channel subfamily, has eight members and is extensively expressed in excitable and non-excitable cells where they perform diverse functions, including sensory transduction, magnesium reabsorption, cell adhesion, and vascular reactivity. TRPM channels have been detected in the kidney, and they participate in regulating osmotic and ion homeostasis. Members of the TRPM family contribute to ischemic kidney injury, but their function in renal fibroblast, a principal mediator of renal fibrosis associated with progressive kidney failure, is unclear. Hence, this study aimed to explore the expression and function of TRPM channels in primary mouse renal fibroblast. We demonstrated that among all TRPM channels, only TRPM 4, 6, and 7 are expressed in the cells. However, the expression of TRPM7 was at least 60% more than TRPM 4 and 6. TRPM7 is a bifunctional protein characterized by ion channel and kinase activity. Treatment of renal fibroblasts with transforming growth factor β(TGF-β) increased the expression of TRPM7. Considering the critical role of renal fibroblast in the development of renal fibrosis and TGF-βas a factor that drives fibrosis in chronic kidney disease, we examined the effect of siRNA-mediated knockdown of TRPM7 on pro-fibrogenic markers and mediators. We demonstrated elevated expression of fibrotic markers fibronectin, vimentin, and collagen type 1 in TGF-βtreated renal fibroblast, an effect attenuated by TRPM7 knockdown. The TGF-β-induced increase in fibrosis markers was accompanied by activation of SMAD3- and STAT3-mediated fibrotic signaling pathways with markedly elevated expression of phosphorylated SMAD3 and STAT3. Knockdown of TRPM7 attenuated expression of phosphorylated SMAD3 and STAT3 in TGF-β-treated renal fibroblast. Migration and proliferation of the cells were elevated when treated with TGF-β. Interestingly, the knockdown of TRPM7 diminished TGF-β-induced renal fibroblast migration and proliferation. Overall, this study suggests that TRPM7 is essential for the profibrotic signaling in renal fibroblast, which is associated with activating the canonical SMAD3 and non-canonical STAT3 pathways of fibrosis. NIH: R01 HL151735-01 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.