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In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome
- 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.
Author: | Zhihuang Zheng, Yao Xu, Ute Krügel, Michael Schaefer, Tilman Grune, Bernd Nürnberg, May-Britt Köhler, Maik Gollasch, Dmitry Tsvetkov, Lajos Markó |
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URN: | urn:nbn:de:gbv:9-opus-64697 |
DOI: | https://doi.org/10.3390/ijms23126870 |
ISSN: | 1422-0067 |
Parent Title (English): | International Journal of Molecular Sciences |
Publisher: | MDPI |
Place of publication: | Basel |
Editor: | Luís Belo, Márcia Carvalho |
Document Type: | Article |
Language: | English |
Date of first Publication: | 2022/06/20 |
Release Date: | 2022/11/16 |
Tag: | CKD; NZO mice; SH045; TRPC6; UUO; fibrosis; inflammation |
GND Keyword: | - |
Volume: | 23 |
Issue: | 12 |
Page Number: | 13 |
Faculties: | Universitätsmedizin / Kliniken und Polikliniken für Innere Medizin |
Licence (German): | Creative Commons - Namensnennung |