Icariin Ameliorates Diabetic Renal Tubulointerstitial Fibrosis by Restoring Autophagy via Regulation of the miR-192-5p/GLP-1R Pathway

Frontiers in Pharmacology

Xuansheng Ding¹  Kang Xiao²  Kaiwei Wang²  Yameng Zhang²  Zhirong Jia²  Shuo Liu²  Yalei Duan² 

[1] Precision Medicine Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China;School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China;

关键词: diabetic kidney disease;    diabetic tubulointerstitial fibrosis;    autophagy;    icariin;    testosterone;    miR-192-5p;   

DOI  :  10.3389/fphar.2021.720387

来源: DOAJ

【 摘 要 】

Tubulointerstitial fibrosis is one of the most common pathological features of diabetic nephropathy. Autophagy, an intracellular mechanism to remove damaged or dysfunctional cell parts and maintain metabolic homeostasis, is inhibited in diabetic neuropathy. Icariin is a traditional Chinese medicine extract known for nourishing the kidney and reinforcing Yang. In this study, we investigated the effects and mechanism of Icariin on renal function, autophagy, and fibrosis in type 2 diabetic nephropathic rats and in high-glucose-incubated human renal tubular epithelial cells and rat renal fibroblasts (in vitro). Icariin improved diabetes, renal function, restored autophagy, and alleviated fibrosis in type 2 diabetic neuropathic rats and in vitro. After we applied autophagy-related gene 5-small interfering RNA, we found that fibrosis improvement by Icariin was related to autophagy restoration. By detecting serum sex hormone levels, and using dihydrotestosterone, siRNA for androgen receptor, and the androgen receptor antagonist Apalutamide (ARN-509), we found that Icariin had an androgen-like effect and restored autophagy and reduced fibrosis by regulating the androgen receptor. In addition, miR-192-5p levels were increased under high glucose but reduced after dihydrotestosterone and Icariin treatment. Furthermore, dihydrotestosterone and Icariin inhibited miR-192-5p overexpression-induced fibrosis production and autophagy limitation. Glucagon-like peptide-1 receptor (GLP-1R) was downregulated by high glucose and overexpression of miR-192-5p and could be restored by dihydrotestosterone and Icariin. By using ARN-509, we found that Icariin increased GLP-1R expression by regulating the androgen receptor. GLP-1R-siRNA transfection weakened the effects of Icariin on autophagy and fibrosis. These findings indicate that Icariin alleviates tubulointerstitial fibrosis by restoring autophagy through the miR-192-5p/GLP-1R pathway and is a novel therapeutic option for diabetic fibrosis.

【 授权许可】

Unknown