Cynapanoside A exerts protective effects against obesity-induced diabetic nephropathy through ameliorating TRIM31-mediated inflammation, lipid synthesis and fibrosis

Obesity is a major predictive factor for the diabetic nephropathy (DN). However, the precise mechanism and therapeutic approach still require to be investigated. Cynapanosides A (CPS-A) is a glycoside derived from the Chinese drug Cynanchum paniculatum that has numerous pharmacological activities, but its regulatory function on obesity-induced kidney disease is still obscure. In the present study, we attempted to explore the renoprotective effects of CPS-A on the established DN in high fat diet (HFD)-fed mice, and the underlying mechanisms. We initially found that CPS-A significantly ameliorated the obesity and metabolic syndrome in mice with HFD feeding. Mice with HFD-induced DN exerted renal dysfunctions, indicated by the elevated functional parameters, including up-regulated blood urea nitrogen (BUN), urine albumin and creatinine, which were significantly attenuated by CPS-A in obese mice. Moreover, histological changes including glomerular enlargement, sclerosis index and collagen deposition in kidney of obese mice were detected, while being strongly ameliorated by CPS-A. Additionally, podocyte loss induced by HFD was also markedly mitigated in mice with CPS-A supplementation. HFD feeding also led to lipid deposition and inflammatory response in renal tissues of obese mice, whereas being considerably attenuated after CPS-A consumption. Intriguingly, we found that tripartite motif-containing protein 31 (TRIM31) signaling might be a crucial mechanism for CPS-A to perform its renoprotective functions in mice with DN. The anti-inflammatory, anti-fibrotic and anti-dyslipidemia capacities of CPS-A were confirmed in the mouse podocytes under varying metabolic stresses, which were however almost abolished upon TRIM31 ablation. These data elucidated that TRIM31 expression was largely required for CPS-A to perform its renoprotective effects. Collectively, our study is the first to reveal that CPS-A may be a promising therapeutic strategy for the treatment of obesity-induced DN or associated kidney disease.