Resolving the mysteries of the renin-angiotensin system in diabetes

Abstract

In 1985, Luetscher et al. reported that an increase in plasma prorenin levels predicts the development of nephropathy and retinopathy in diabetic patients, and since then many studies have reported similar findings. However, why an elevated plasma prorenin level predicts diabetic microvascular complications remained unclear. On the other hand, low plasma renin levels were observed when diabetic microvascular complications developed, suggesting that it was not necessary for the circulating renin-angiotensin system (RAS) to be elevated. Nevertheless, many clinical studies have reported that RAS inhibitors have a protective effect on the kidneys of diabetic patients. These findings suggest that in diabetic kidneys, the tissue RAS must be activated independently of the circulating RAS. However, the mechanism accounting for the circulating RASindependent regulation of the tissue RAS also remained undetermined. Previous studies in transgenic rats over-expressing prorenin in the liver showed that elevated plasma prorenin levels caused end-organ damage in the heart and kidneys without hypertension or plasma RAS activation. An intravenous infusion of prorenin had no effect on blood pressure or plasma renin activity. Thus, prorenin can stimulate the tissue RAS and subsequent end-organ damage independently of the circulating RAS. We then focused on prorenin as a key factor in the development of diabetic microvascular complications.