Senolytic combination of dasatinib and quercetin protects against diabetic kidney disease by activating autophagy toalleviate podocyte dedifferentiation via the Notch pathway.

Abstract

The senolytics dasatinib and quercetin (DQ) alleviate age‑related disorders. However, limited information is available regarding the effects of DQ on diabetic kidney disease (DKD). The present study aimed to explore the effects of DQ on DKD and its potential molecular mechanism(s). Dasatinib (5mg/kg) and quercetin (50mg/kg) were administered to diabetic db/db mice by gavage for 20weeks. Body weight, urine albumin‑creatinine ratio (ACR), serum creatinine (Scr), and blood urea nitrogen (BUN) were recorded at the indicated time periods. Periodic acid‑Schiff and Masson's staining were performed to assess the histopathological changes of kidney tissues. Immunohistochemical analysis, immunofluorescence and western blotting were performed to evaluate the expression levels of extracellular matrix (ECM) proteins, autophagic and podocyte differentiation‑related proteins. In addition, mouse podocytes were administered with high‑glucose, DQ and 3‑methyladenine (3‑MA), and the expression levels of autophagic and podocyte differentiation‑related proteins were measured. Moreover, following overexpression of the Notch intracellular domain (NICD), the expression levels of NICD, autophagic and podocyte differentiation‑related proteins were further assessed. DQ significantly reduced the body weight, blood glucose, ACR, Scr and BUN levels and improved the histopathological changes induced in diabetic db/db mice. In addition, DQ caused a significant downregulation of the expression levels of the ECM proteins, improved autophagy and induced an upregulation of the expression levels of podocyte differentiation‑related proteins. Administration of 3‑MA to mice significantly reduced podocyte differentiation, and overexpression of NICD could reverse the effects of DQ on autophagy and podocyte differentiation invitro. The present study suggests that DQ protects against DKD by activation of autophagy to alleviate podocyte dedifferentiation via the Notch pathway.