Activated prorenin as a therapeutic target for diabetic nephropathy.

High plasma prorenin levels in diabetic patients predict microvascular complications, but the mechanism of the connection between these factors has remained unclear. (Pro)renin receptors were recently found in the human kidney, and their distribution in the kidneys include the mesangium and podocytes. The binding of prorenin to the (pro)renin receptor triggers two major pathways: the angiotensin II-dependent pathway as a result of the conversion of prorenin to the active form of prorenin through a conformational change, and the angiotensin II-independent, (pro)renin-receptor-dependent intracellular mitogen-activated protein kinase pathway. To investigate whether the (pro)renin-receptor-dependent pathways contribute to the pathophysiology of the end-organ damage that occurs in diabetes, the handle region peptide, which binds to the receptor and competitively inhibits prorenin from binding to the receptor, was administered to rats with streptozotocin-induced type I diabetes and to a model of type II diabetes, db/db mice. The handle region peptide significantly inhibited the development of end-organ damage in these diabetic animals, and had a greater benefit than angiotensin-converting enzyme inhibitors in diabetic angiotensin II-type 1a-receptor-deficient mice. In addition, the infusion of the handle region peptide in animals with streptozotocin-induced type I diabetes significantly regressed the nephropathy that had already occurred. These results suggest that prorenin and the (pro)renin receptor play a pivotal role in the pathophysiology of diabetic nephropathy. Receptor-bound prorenin may prove useful as an important therapeutic target for the prevention and regression of end-organ damage in patients with diabetes.