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

International Journal of Molecular Sciences

Dmitry Tsvetkov¹  Yao Xu¹  Tilman Grune²  Maik Gollasch³  Zhihuang Zheng³  Bernd Nürnberg⁴  May-Britt Köhler⁵  Lajos Markó⁵  Michael Schaefer⁶  Ute Krügel⁶ 

[1]Department of Internal Medicine and Geriatrics, University Medicine Greifswald, 17475 Greifswald, Germany

[2]Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany

[3]Department of Nephrology/Intensive Care, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany

[4]Department of Pharmacology, Experimental Therapy and Toxicology and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, 72076 Tübingen, Germany

[5]Experimental and Clinical Research Center, a Joint Cooperation of the Charité—University Medicine Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany

[6]Rudolf Boehm Institute for Pharmacology and Toxicology, Leipzig University, 04107 Leipzig, Germany

关键词: TRPC6;    UUO;    NZO mice;    inflammation;    fibrosis;    CKD;   

DOI  :  10.3390/ijms23126870

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown