Nimbidiol ameliorates adverse renal remodeling and dysfunction in diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. DN is characterized by excess accumulation of extracellular matrix (ECM) proteins in the glomeruli and tubulointerstitium leading to progressive fibrosis and loss of renal function. Matrix metalloproteinases (MMPs) are a group of zinc-dependent endopeptidases that regulate synthesis and degradation of the ECM. Previously, we have shown that elevated MMP-9 and -13 cause adverse ECM remodeling in type-1 diabetic kidney. Nimbidiol is a diterpenoid derived from the root/stem-bark of the medicinal plant ‘Neem’ (Azadirachta indica) and is known to possess anti-diabetic properties. In in vivo cancer studies, neem extract has been reported to regulate ECM proteins and suppress metastasis by modulating MMP-9 and -2 expressions. The purpose of the present study was to investigate the potential role of Nimbidiol to modulate MMP-9 level thus regulate ECM protein accumulation and renal fibrosis during type-1 DN. In order to accomplish this, C57BL6/-Ins2Akita/J, (Akita) mice representing type-1 diabetes and C57BL6/J (WT) mice aged 12-14 weeks were treated without or with Nimbidiol (0.4 mg kg-1day-1) using micro-osmotic pump for eight consecutive weeks. Compared to the WT group, Akita mice showed distinct renovascular remodeling as evidenced by increased MMP-9 expression, ECM protein accumulation and elevated pro-fibrotic markers. The changes were associated with functional impairment that includes elevated renovascular resistive index (RI), reduced renal cortical blood flow and glomerular filtration rate (GFR). Nimbidiol treatment alleviated the adverse pathophysiological changes by decreasing collagen and fibronectin and increasing elastin expression. Our results suggest that Nimbidiol ameliorates renal fibrosis by reducing MMP-9 and ECM protein accumulation and improves renal function.