In vivo inhibition of TRPC6 by SH045 attenuates renal fibrosis in a New Zealand Obese (NZO) mouse model of metabolic syndrome

Zheng, Z.; Xu, Y.; Krügel, U.; Schaefer, M.; Grune, T.; Nürnberg, B.; Köhler, M.B.; Gollasch, M.; Tsvetkov, D.; Marko, L.

In vivo inhibition of TRPC6 by SH045 attenuates renal fibrosis in a New Zealand Obese (NZO) mouse model of metabolic syndrome

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Item Type:	Article
Title:	In vivo inhibition of TRPC6 by SH045 attenuates renal fibrosis in a New Zealand Obese (NZO) mouse model of metabolic syndrome
Creators Name:	Zheng, Z., Xu, Y., Krügel, U., Schaefer, M., Grune, T., Nürnberg, B., Köhler, M.B., Gollasch, M., Tsvetkov, D. and Marko, L.
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.
Keywords:	TRPC6, UUO, NZO Mice, Inflammation, Fibrosis, CKD, SH045, Animals, Mice
Source:	International Journal of Molecular Sciences
ISSN:	1422-0067
Publisher:	MDPI
Volume:	23
Number:	12
Page Range:	6870
Date:	20 June 2022
Official Publication:	https://doi.org/10.3390/ijms23126870
PubMed:	View item in PubMed

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