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 (Col1a1, Col3a1, Col4a1, 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 -smooth muscle actin (-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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:89481 |
| Date | 02 February 2024 |
| Creators | Zheng, Zhihuang, Xu, Yao, Krügel, Ute, Schaefer, Michael, Grune, Tilman, Nürnberg, Bernd, Köhler, May-Britt, Gollasch, Maik, Tsvetkov, Dmitry, Marko, Lajos |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 6870 |
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