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

Abstract

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.

Oxidative Stress and NRF2/KEAP1/ARE Pathway in Diabetic Kidney Disease (DKD): New Perspectives

“…Another studied flavonoid is Icariin, found in Epimedium plant species. It possesses many biological roles, while in DKD, it shows an anti-fibrotic and antioxidant effect, the last one in an NRF2 partially dependent pathway [ 165 , 166 ]. Other representatives that can trigger the NRF2/KEAP1/ARE pathway are Diphlorethohydroxycarmalol, derived from Ishige okamurae, a species of algae [ 167 ], Genistein [ 6 ], Hesperetin [ 168 ], Myricetin [ 169 ] and Digitoflavone (3,0,4,5,7-tetrahydroxyflavone) [ 170 , 171 ].…”

Molecular Mechanistic Pathways Targeted by Natural Compounds in the Prevention and Treatment of Diabetic Kidney Disease

“…Jia et al found that icariin can induce autophagy and reduce renal fibrosis in the DKD models, and its mechanism is related to the reduction of miR-192-5p, its overexpression inhibited glucagon-like peptide 1 receptor (GLP-1R), induced p-mTOR expression, and increasing the expression of collagen I, α-SMA, and FN. Icariin can alleviate DKD renal fibrosis by restoring autophagy through the miR-192-5p/GLP-1R pathway [ 137 ]. In addition, Zang et al found that miR-122-5p also plays a role in the development of DKD, miR-122-5p inhibited forkhead box protein P2 (FOXP2) transcription, resulting in decreased cell viability, and inhibit E-cadherin expression, increasing α-SMA expression.…”

The critical role of dysregulated autophagy in the progression of diabetic kidney disease

“…Cyclocarya paliurus triterpenic acids or reduced expression of thioredoxin interacting protein (TXNIP) acted through mTOR or in combination with the AMPK pathway to induce autophagy ( Huang et al, 2016 ; Zhang et al, 2019 ). In contrast, the Chinese herbal extract icariin from Epimedium restored autophagy and attenuated renal tubulointerstitial fibrosis by targeting miR-192-5p/GLP-1R (GLP-1 receptor) in a DKD model ( Jia et al, 2021 ). At the same time, the overexpression of TXNIP (one of the factors of autophagy) induced by high glucose led to autophagy dysfunction and participated in the occurrence of DKD ( Huang et al, 2014 ).…”