In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome.

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.

• Authors: Zhihuang Zheng, Yao Xu, Ute Krügel, Michael Schaefer, Tilman Grune, Bernd Nürnberg, May-Britt Köhler, Maik Gollasch, Dmitry Tsvetkov, Lajos Markó
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 12 (Jun 20 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35743312 (Publication Type: Journal Article)

Chemical References

• TRPC6 Cation Channel
• Trpc6 protein, mouse

Topics

• Animals
• Disease Models, Animal
• Fibrosis
• Hypertension (metabolism)
• Kidney (metabolism)
• Kidney Diseases (etiology, genetics)
• Metabolic Syndrome (complications, drug therapy, metabolism)
• Mice
• Mice, Obese
• New Zealand
• Obesity (complications, drug therapy, metabolism)
• TRPC6 Cation Channel (metabolism)
• Ureteral Obstruction (complications, drug therapy, genetics)