Nicousamide attenuates renal dysfunction and glomerular injury in remnant kidneys by inhibiting TGF-β1 internalisation and renin activity

Abstract

Nicousamide has been shown to exert renal protective effects against diabetic nephropathy and has moved to a phase II clinical trial in China for diabetic nephropathy indication. To expand its clinical indications, 5/6-nephrectomised rats were used to mimic glomerular and vascular sclerosis and tubulointerstitial scarring, with subsequent progression towards end-stage renal disease. Adult Wistar rats underwent 5/6 nephrectomy to induce the development of chronic kidney disease, with a sham operation performed as a control. The nephrectomised animals were treated orally with either saline, nicousamide (7.5,15, or 45 mg/kg), benazepril (4 mg/kg), or losartan (10 mg/kg) daily for 20 weeks. At 8, 16, and 20 weeks of treatment, blood pressure was measured in each animal, and blood and urine samples were collected for biochemical analysis, while kidney remnants were collected for histological examination. Levels of fibronectin and transforming growth factor beta 1 (TGF-β1) were measured in kidneys by immunohistochemistry. Renin activity in the plasma was measured by an enzyme-linked immunosorbent assay. The results showed that nicousamide treatment significantly reduced systemic hypertension, proteinuria, and blood urea nitrogen (P < 0.05), effectively alleviated glomerular sclerosis scores and tubulointerstitial injuries in a dose-dependent manner (P < 0.01), and markedly decreased fibronectin and TGF-β1 levels in kidney tissues of the 5/6-nephrectomised animals. In vitro studies suggested that nicousamide could moderately inhibit the renin activity and strongly block the TGF-β1 internalisation into fibroblast cells. In summary, nicousamide may protect from renal failure through dual targeting, which involves a TGF-β1-dependent mechanism and inhibition of renin activity.