Reno-protective effect of GLP-1 receptor agonists : silencing the cross-talk between TRPC6 and NADPH oxidases in diabetic rats

Abstract

Background: Diabetic kidney disease (DKD) is a life-threatening complication of Diabetes. It is characterized by podocyte injury which compromises the glomerular filtration barrier, thus, leading to proteinuria. Podocyte injury is thought to be mediated by reactive oxygen species (ROS) production via NADPH oxidases. DUOX 1 and 2 are NADPH oxidase isoforms that acquire in their structure a calcium binding site. Calcium signaling through TRPC channels is of key importance in podocyte function and disruption of its homeostasis leads to cytoskeleton disorganization, foot process effacement and disruption of slit diaphragm. Evidence from literature suggests that TRPC6 channels can be activated by NADPH oxidases eventually leading to diabetic kidney injury. On the other hand, GLP-1 was found to regulate calcium channels in pancreatic cells. Besides, hypoglycemic treatments such as GLP-1 receptor agonists (GLP-1RA) have been shown to exert a reno-protective effect, yet this mechanism is still not well elucidated. Herein, we aim to investigate the role of TRPC6 channel and NADPH oxidases in kidney injury and the effect of GLP-1RA on reversing this process. Design Sprague Dawley rats were allocated into five groups: control, STZ induced type I diabetic group, STZ induced type 1 diabetic group treated with Metformin or GLP-1RA or combination for duration of 8 weeks. Functional, histopathological, biochemical and molecular studies were performed on kidney tissues from all groups. Results GLP-1RA treatment ameliorates kidney injury. This was transduced by a reduction in BUN, SCr and proteinuria. PAS and MT staining revealed reduced collagen deposition and fibrosis. This result was consistent with mRNA expression of fibronectin in kidney tissues. In addition, nephrin mRNA expression was restored upon treatment. Moreover, we noticed decreased ROS production, NADPH oxidases activity and mRNA expression of DUOXs, with reduced expression of TRPC6 but not TRPC3 upon treating with GLP-1RA. Conclusion GLP-1RA seems to delay diabet