Liu Zhenyu, Wang Weili, Li Xueqin, Tang Sha, Meng Dongwei, Xia Wenli, Wang Hong, Wu Yuzhang, Zhou Xinyuan, Zhang Jingbo
Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, PR China.
School of Medicine, Chongqing University, Chongqing 400030, PR China; College of Bioengineering, Chongqing University, Chongqing 400044, PR China.
Phytomedicine. 2022 Jun;100:154067. doi: 10.1016/j.phymed.2022.154067. Epub 2022 Mar 21.
Chronic kidney disease (CKD), characterized by renal fibrosis, is a global refractory disease with few effective therapeutic strategies. It has been reported that capsaicin exerts many pharmacological effects including liver and cardiac fibrosis. However, whether capsaicin plays a therapeutic role in renal fibrosis remains unclear.
We investigated antifibrotic effects of capsaicin in two mouse renal fibrosis models as follows: C57BL/6J mice were subjected to unilateral ureteral obstruction (UUO) and fed with an adenine-rich diet. We uncovered and verified the mechanisms of capsaicin in human proximal tubular epithelial cells (HK2). We mainly used histochemistry, immunohistochemistry and immunofluorescence staining, western blot assay, biochemical examination and other tools to examine the effects of capsaicin on renal fibrosis and the underlying mechanisms.
Capsaicin treatment significantly alleviated fibronectin and collagen depositions in the tubulointerstitium of the injured kidneys from UUO and adenine-fed mice. Meanwhile, capsaicin treatment obviously reduced α-SMA expression. Moreover, capsaicin treatment dramatically protected against the phenotypic alteration of tubular epithelial cells by increasing E-cadherin expression and decreasing vimentin expression during renal fibrosis. Mechanistically, capsaicin treatment effectively suppressed α-SMA and vimentin expressions but promoted E-cadherin expression in HK2 cells mainly through the inhibition of TGF-β1-Smad2/3 signaling.
Capsaicin significantly ameliorated renal fibrosis possibly by retarding the activation of myofibroblasts and protecting against the phenotypic alteration of tubular epithelial cells mainly through the inhibition of TGF-β1-Smad2/3 signaling. Thus, our findings may provide a new insight into the clinical application of capsaicin in renal fibrosis.
慢性肾脏病（CKD）以肾纤维化为特征，是一种全球难治性疾病，有效治疗策略较少。据报道，辣椒素具有多种药理作用，包括对肝脏和心脏纤维化的作用。然而，辣椒素在肾纤维化中是否发挥治疗作用仍不清楚。
我们在两种小鼠肾纤维化模型中研究了辣椒素的抗纤维化作用，具体如下：将C57BL/6J小鼠进行单侧输尿管梗阻（UUO）并给予富含腺嘌呤的饮食。我们揭示并验证了辣椒素在人近端肾小管上皮细胞（HK2）中的作用机制。我们主要使用组织化学、免疫组织化学和免疫荧光染色、蛋白质免疫印迹分析、生化检测等方法来研究辣椒素对肾纤维化的影响及其潜在机制。
辣椒素治疗显著减轻了UUO和腺嘌呤喂养小鼠受损肾脏肾小管间质中纤连蛋白和胶原蛋白的沉积。同时，辣椒素治疗明显降低了α-SMA的表达。此外，在肾纤维化过程中，辣椒素治疗通过增加E-钙黏蛋白表达和降低波形蛋白表达，显著保护肾小管上皮细胞的表型改变。机制上，辣椒素治疗主要通过抑制TGF-β1-Smad2/3信号通路，有效抑制HK2细胞中α-SMA和波形蛋白的表达，但促进E-钙黏蛋白的表达。
辣椒素可能主要通过抑制TGF-β1-Smad2/3信号通路，延缓肌成纤维细胞的激活并保护肾小管上皮细胞的表型改变，从而显著改善肾纤维化。因此，我们的研究结果可能为辣椒素在肾纤维化临床应用中提供新的见解。
