Department of Nephrology/Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany.
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.
Int J Mol Sci. 2022 Jun 20;23(12):6870. doi: 10.3390/ijms23126870.
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 (, , , , , ) and chemokines (, , ) 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.
代谢综合征是一个全球性的重大公共卫生挑战，与不良的肾脏和心血管结局密切相关。现已发现，瞬时受体电位阳离子通道亚家族 C 成员 6（TRPC6）的抑制可改善单侧输尿管梗阻（UUO）加速的肾脏纤维化中的肾脏结局。因此，TRPC6 的药理学抑制可能是高血压和代谢综合征进行性肾小管间质纤维化的一种有前途的治疗干预措施。在本研究中，我们假设新型选择性 TRPC6 抑制剂 SH045（larixyl N-甲基氨基甲酸酯）可改善新西兰肥胖（NZO）小鼠模型中的 UUO 加速肾脏纤维化，该模型是代谢综合征的多基因模型。与 vehicle 处理的动物相比，SH045 对 NZO 小鼠 UUO 肾脏中 TRPC6 的体内抑制显著降低了促纤维化标志物（、、、、、）和趋化因子（、、）的 mRNA 表达。SH045 处理的 UUO 小鼠肾脏中的细胞间黏附分子 1（ICAM-1）和α-平滑肌肌动蛋白（α-SMA）表达减少。此外，SH045 处理的 NZO 小鼠的肾脏炎症细胞浸润（F4/80+和 CD4+）和肾小管间质纤维化（天狼星红和纤维连接蛋白染色）得到改善。我们得出结论，TRPC6 的药理学抑制可能是治疗高血压和代谢综合征进行性肾小管间质纤维化的一种有前途的抗纤维化治疗方法。
