Description:
Metabolic syndrome is a significant worldwide public health challenge and is inextricablylinked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potentialcation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in theunilateral ureteral obstruction (UUO) of accelerated renal fibrosis. Therefore, the pharmacological inhibitionof TPRC6 could be a promising therapeutic intervention in the progressive tubulo-interstitialfibrosis in hypertension and metabolic syndrome. In the present study, we hypothesized that thenovel selective TRPC6 inhibitor SH045 (larixyl N-methylcarbamate) ameliorates UUO-acceleratedrenal fibrosis in a New Zealand obese (NZO) mouse model, which is a polygenic model of metabolicsyndrome. The in vivo inhibition of TRPC6 by SH045 markedly decreased the mRNA expression ofpro-fibrotic markers (Col1a1, Col3a1, Col4a1, Acta2, Ccn2, Fn1) and chemokines (Cxcl1, Ccl5, Ccr2) inUUO kidneys of NZO mice compared to kidneys of vehicle-treated animals. Renal expressions ofintercellular adhesion molecule 1 (ICAM-1) and -smooth muscle actin (-SMA) were diminished inSH045- versus vehicle-treated UUO mice. Furthermore, renal inflammatory cell infiltration (F4/80+and CD4+) and tubulointerstitial fibrosis (Sirius red and fibronectin staining) were amelioratedin SH045-treated NZO mice. We conclude that the pharmacological inhibition of TRPC6 mightbe a promising antifibrotic therapeutic method to treat progressive tubulo-interstitial fibrosis inhypertension and metabolic syndrome.