Effects of pressure-dependent regulation of prorenin synthesis and secretion on progression of diabetic nephropathy

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We found that when a site-specific binding protein interacts with the "handle" region of the prorenin prosegment, the prorenin molecule undergoes a conformational change to its enzymatically active state. This non-proteolytic activation is completely blocked by a decoy peptide with the "handle" region structure, which competitively binds to such a binding protein. Even though diabetic animals have high plasma prorenin levels and low plasma renin levels, suggesting a suppressed circulating RAS, angiotensin II type 1 receptor blockers have a beneficial effect in preventing the development and progression of diabetic organ damage. We examined the hypotheses that the non-proteolytic activation of prorenin plays a significant role in diabetic organ damage. Streptozotocin-induced diabetic rats were treated with subcutaneous administration of "handle" region peptide. Metabolic and renal histological changes and the renin-angiotensin system components in the plasma and kidneys were determined … More at 8,16, and 24 weeks following streptozotocin treatment. Kidneys of diabetic rats contained increased angiotensin I and II without any changes in renin, angiotensin converting enzyme, or angiotensinogen synthesis. However, treatment with the "handle" region peptide decreased the renal content of angiotensin I and II and completely inhibited the development of diabetic nephropathy without affecting hyperglycemia. We propose that the non-proteolytic activation of prorenin may be a significant mechanism of diabetic nephropathy. The mechanism and substances causing non-proteolytic activation of prorenin may serve as important therapeutic target for the prevention of diabetic organ damage. Also, if the complex of prorenin and its receptor is also able to activate the ERK1/ERK2 pathways independently of the RAS activation as proposed by Nguyen et al., it is possible that an inhibitor of complex formation between the receptor and prorenin can completely prevent the development of diabetic organ damages through the inhibition of not only the RAS activation but also the RAS-independent ERK activation. Less