The Importance of the RAS Interacting with the HGF/C-Met Receptor System in Hypertensive Type 2 Diabetes Mellitus

Abstract

The classic renin-angiotensin system (RAS) is described as a circulating hormone system with primary roles in the regulation of blood pressure, body water balance and thirst and control over vasopressin and aldosterone release. Recently local tissue RASs have been identified with regulatory physiological functions and also with pathophysiological processes including fibrosis, inflammation and dysfunctional cell proliferation. There is a strong correlation between organs vulnerable to diabetic–induced hyperglycemic injury (eg. kidney and retina) and the over activation of local RASs.  Increased angiotensin II concentrations in these tissues promotes hypertension and end-organ damage in at least two ways: 1) By activating AT1 receptor proteins thus inducing changes in local blood flow and tissue hydration and 2) Exacerbating hyperglycemic-induced oxidative stress, elevated polyol and hexosamine pathway variability and facilitating glycation end-products. Thus, inhibition of the RAS has become an important treatment approach to control diabetic related hypertension, nephropathy and to a lesser extent retinopathy. The present review emphasizes the recently established importance of the hepatocyte growth factor (HGF)/c-Met receptor system interacting with the RAS in Type 2 diabetes and their likely contribution to end-organ damage. A hypothesis is offered concerning how the pancreatic RAS may affect dimerization of HGF and in turn activation of the c-Met receptor to promote β cell proliferation and insulin synthesis. We conclude with details concerning the development of an AngIV-based small molecule HGF mimetic designed to act as an insulinotropic factor.