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

**Zhihuang Zheng 1,2 , Yao Xu 3, Ute Krügel <sup>4</sup> , Michael Schaefer 4, Tilman Grune 5,6, Bernd Nürnberg <sup>7</sup> , May-Britt Köhler 2, Maik Gollasch 1,3,\*, Dmitry Tsvetkov 3,\* and Lajos Markó 2,6,8,9,\***


**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

**Citation:** Zheng, Z.; Xu, Y.; Krügel, U.; Schaefer, M.; Grune, T.; Nürnberg, B.; Köhler, M.-B.; Gollasch, M.; Tsvetkov, D.; Markó, L. In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome. *Int. J. Mol. Sci.* **2022**, *23*, 6870. https://doi.org/ 10.3390/ijms23126870

Academic Editors: Luís Belo and Márcia Carvalho

Received: 18 March 2022 Accepted: 16 June 2022 Published: 20 June 2022

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