1. In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome.
- Author
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Zheng Z, Xu Y, Krügel U, Schaefer M, Grune T, Nürnberg B, Köhler MB, Gollasch M, Tsvetkov D, and Markó L
- Subjects
- Animals, Disease Models, Animal, Fibrosis, Kidney metabolism, Mice, Mice, Obese, New Zealand, Obesity complications, Obesity drug therapy, Obesity metabolism, TRPC6 Cation Channel metabolism, Hypertension metabolism, Kidney Diseases etiology, Kidney Diseases genetics, Metabolic Syndrome complications, Metabolic Syndrome drug therapy, Metabolic Syndrome metabolism, Ureteral Obstruction complications, Ureteral Obstruction drug therapy, Ureteral Obstruction genetics
- Abstract
Metabolic syndrome is a significant worldwide public health challenge and is inextricably linked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potential cation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in the unilateral ureteral obstruction (UUO) of accelerated renal fibrosis. Therefore, the pharmacological inhibition of TPRC6 could be a promising therapeutic intervention in the progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome. In the present study, we hypothesized that the novel selective TRPC6 inhibitor SH045 (larixyl N-methylcarbamate) ameliorates UUO-accelerated renal fibrosis in a New Zealand obese (NZO) mouse model, which is a polygenic model of metabolic syndrome. The in vivo inhibition of TRPC6 by SH045 markedly decreased the mRNA expression of pro-fibrotic markers ( Col1α1 , Col3α1 , Col4α1 , Acta2 , Ccn2 , Fn1 ) and chemokines ( Cxcl1 , Ccl5 , Ccr2 ) in UUO kidneys of NZO mice compared to kidneys of vehicle-treated animals. Renal expressions of intercellular adhesion molecule 1 (ICAM-1) and α-smooth muscle actin (α-SMA) were diminished in SH045- versus vehicle-treated UUO mice. Furthermore, renal inflammatory cell infiltration (F4/80+ and CD4+) and tubulointerstitial fibrosis (Sirius red and fibronectin staining) were ameliorated in SH045-treated NZO mice. We conclude that the pharmacological inhibition of TRPC6 might be a promising antifibrotic therapeutic method to treat progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome.
- Published
- 2022
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