Critical roles of (pro)renin receptor-bound prorenin in diabetes and hypertension: sallies into therapeutic approach

Abstract

High plasma prorenin levels in diabetic patients predict microvascular complications, but the mechanism of the connection between them has remained unclear. (Pro)renin receptors were recently found in the human kidney, and their distribution in various organs, including the heart, has been identified. Binding of prorenin to the (pro)renin receptor triggers two major pathways: the angiotensin II-dependent pathway as a result of conversion of prorenin to the active form of prorenin by a conformational change, and the angiotensin II-independent intracellular pathway via the (pro)renin receptor. To investigate whether the (pro)renin-receptor-dependent pathways contribute to the pathophysiology of the end-organ damage that occurs in diabetes and hypertension, a (pro)renin receptor blocker (PRRB), which binds to the receptor and competitively inhibits prorenin binding to the receptor, was administered to rats with streptozotocin-induced diabetes and to stroke-prone spontaneously hypertensive rats. PRRB significantly inhibited the development and progression of end-organ damage in these animal models of diabetes and hypertension, and it was of greater benefit than conventional inhibitors in relation to the renin-angiotensin system in diabetic angiotensin II-type 1a-receptor-deficient mice. The (pro)renin receptor may prove useful as an important therapeutic target for the prevention and regression of end-organ damage in diabetes and hypertension.