Angiopoietin-like protein 3 deficiency combined with valsartan administration protects better against podocyte damage in streptozotocin-induced diabetic nephropathy mice

Abstract

Diabetic nephropathy (DN) is a common leading cause of end-stage renal disease (ESRD). Podocyte injury is a major pathogenesis of DN. Pharmacological inhibition of the renin-angiotensin-aldosterone system (RAAS) is insufficient to fully prevent the development of ESRD. The present investigation aims to evaluate the protective function of valsartan, an angiotensin receptor blocker, alone and in combination with angiopoietin-like protein 3 (Angptl3) knockout against renal damage and podocyte injury in streptozotocin (STZ)-induced diabetic mice. The mice were divided into four groups: normal control group, STZ-induced DN group, valsartan + DN group (val, 100 mg/kg, po), and Angptl3-/- + valsartan + DN group. Tests on kidney function, renal pathology, podocyte ultrastructure, podocyte apoptosis, reactive oxygen species (ROS) production, and autophagy were performed. The combined Angptl3 knockout/valsartan treatment significantly attenuated diabetes-induced renal pathological damage and improved podocyte ultrastructure compared with valsartan alone. The combined administration ameliorated glomerular injury by increasing nephrin, podocin, and CD2-associated protein (CD2AP) expression levels and inhibiting podocyte loss by apoptosis. Compared with valsartan alone, Angptl3-/- and valsartan combination therapy significantly improved the renal function, as demonstrated by decreasing levels of serum urea nitrogen, creatinine, and urinary albumin. Additionally, the combination treatment significantly activated autophagy and reduced the ROS production than valsartan alone. These findings highlight the role of valsartan to Angptl3 knockout could have much better outcome that opens the future for drugs that could inhibit Angptl3.

Keywords: Angptl3; Autophagy; DN; Podocyte; Valsartan.