African Americans carry a 3-6 fold increased risk of developing nephropathy as a complication of diabetes mellitus (DM), essential hypertension (HTN), and probably other conditions. Although an increased frequency and severity of HTN and socioeconomic factors that limit health care probably contribute, multiple observations indicate that more important alternative factors are also involved. Fields ranging from epidemiology and therapeutic trials to molecular biology and genetics indicate that the renin-angiotensin system (RAS) contributes to the risk of nephropathy via mechanisms that include but go beyond HTN, perhaps involving the contribution of the RAS to growth and repair hyperplasia, and hypertrophy. Our application is based on several unanticipated observations. First, in healthy African Americans, age- adjusted renal plasma flow (RPF) was substantially less than in Caucasians, assessed in an identical protocol. Moreover, despite a high salt diet, African Americans displayed an enhanced renal vasodilator response to angiotensin-converting enzymic (ACE) inhibition with captopril, which enhanced renal vascular responsiveness to angiotensin II (Ang II). This pattern (which clearly differs from that in Caucasians and is similar to our preliminary observations in patients with DM) suggests activation of the RAS. Second, in our non-insulin- dependent Type 2 DM patients, our preliminary data suggest a range of hitherto unrecognized RAS abnormalities reflecting inappropriate activation and autonomous renin release. Most surprising is the paradoxical extreme RAS activation at the renal tissue level Type 2 DM patients with very low plasma renin activity (PRA) and nephropathy. Evidence for a functional contribution comes from hemodynamic measurements made during pharmacological interruption of the RAS with ACE inhibitors and Ang II antagonists, and during Ang II infusion. In Type 2 DM, race is a critical determinant of risk. Third, we have made observations which indicate that acute hyperglycemia activates the intrarenal system and induces striking Ang II-dependent vasoconstriction. Our hypothesis is that the increase in risk of nephropathy represents an interaction between genetic predisposition based on the increased frequency of an angiotensinogen (AGT) gene polymorphism that favors renin system activation, an action of obesity and insulin resistance to amplify the effect of the polymorphism on AGT; and the renal effects of hyperglycemia to activate the intrarenal system in a setting which would favor local intrarenal Ang II production. Our goal in this study is to explore preliminary evidence that RAS activation accounts for many Type 2 DM features involving renal risk, and racial differences in risk.
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