Diabetes-Induced vascular complications : cross-talk between Kallikrein-Kinin System and Leptin Receptor through SphK-S1P pathway

Abstract

Diabetes mellitus is among the leading causes of deaths worldwide with a huge health care cost due to its high morbidity and associated complications. Since the discovery of kallikrein-kinin system (KKS) as a potent vasodilator, many studies focused on understanding the pathophysiological roles of this system. There is a strong evidence associating KKS components with different pathological conditions related to diabetes. In this study, we aimed at studying the involvement of KKS in diabetes-induced vascular diseases. We studied our aim through four sub-objectives. We employed global protein profiling to study the effect of diabetes on the aorta and kidney, and the effect of BK and leptin on vascular smooth muscle cells (VSMC). Additionally, we used western blot, qPCR analyses, and confocal microscopy to examine the signaling of BK, S1p, and leptin in VSMC from rats and mouse models. Our findings showed that diabetes directly induces the expression of kininogen, the precursor of Bradykinin (BK), in the VSMC of the aorta eliminating the vasodilatory possible effect of BK on endothelial cells. The upregulation of BK-producing proteins in the VSMC proposes a mechanism by which BK exerts paradoxical deleterious effects on the physiology of VSMC and subsequently the vessels through promoting inflammation and fibrotic disease. On the other hand, BK induces the expression of two fibrotic proteins, Connective tissue growth factor (Ctgf) and Fibronectin (Fn1), through modulating the activity of reactive oxygen species (ROS)-ERK-SphK1-S1p axis. Moreover, BK induces the expression of leptin pathway, which is responsible for relaying the signal transduction of BK on fibrotic proteins. The regulation of leptin downstream of BK proposes a novel role of the KKS in actin remodeling induced vascular hypertrophy in VSMC. Taken together, the study outcomes show a possible mechanism by which BK could contribute to the development of the diabetes-induced vascular disease.