Morin hydrate attenuates adenine-induced renal fibrosis via targeting cathepsin D signaling

Abstract

Lysosomal proteases such as cathepsins B, D, L, and K can regulate the process of fibrosis in most of the organs. However, the role of cathepsin D (CATD) in kidney fibrosis and corresponding chronic kidney disease (CKD) is still unknown. We investigated whether CATD immunomodulation using morin hydrate (MH) can attenuate kidney fibrosis in CKD. Here, CKD was developed by an oral dosage of adenine (AD) in the mice model. Histopathological detection using H & E and Oil-Red-O staining revealed tissue deposition. An escalation in serum creatinine, albumin, and blood urea nitrogen (BUN) revealed a failure in kidney function. An increase in fibrosis was determined using protein analysis and mRNA analysis of MMP-9 and MMP-2 respectively. Both immunoblot analysis and histological analysis indicated that MH immunomudulated CATD expression in AD treated kidneys. With docking analysis, we found MH can bind with the catalytic core of CATD with binding efficiency of −6.83 kcal/mol. Further, MH prevented AD mediated fibrosis by reducing collagen fragmentation as evidenced by the decrease in MMP-2 (P < 0.05) and MMP-9 (P < 0.001) protein levels. MH lowered the levels of inflammation by reducing the AD enhanced expression of MCP-1 and COX-2 nearly threefold. MH treatment increased body weight, enhance kidney function, and improved survival by nearly 150% compared to AD treated mice. CATD inactivation by MH after AD treatment resulted in decreased ECM degradation, fibrosis, and inflammation which resulted in improved renal function and survival.