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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. and Xu, Y. and Krügel, U. and Schaefer, M. and Grune, T. and Nürnberg, B. and Köhler, M.B. and Gollasch, M. and 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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