Contribution of nonproteolytically activated prorenin in glomeruli to hypertensive renal damage

• Published in: Journal of the American Society of Nephrology 2006-09, Vol.17 (9), p.2495-2503
• Main Authors: ICHIHARA, Atsuhiro, KANESHIRO, Yuki, TAKEMITSU, Tomoko, SAKODA, Mariyo, NAKAGAWA, Tsutomu, NISHIYAMA, Akira, KAWACHI, Hiroshi, SHIMIZU, Fujio, INAGAMI, Tadashi
• Format: Article
• Language: English
• Subjects: Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Collagen Type IV - biosynthesis; Enzyme Activation; Experimental diseases; Hypertension - physiopathology; Immunohistochemistry; Kidney - pathology; Kidney Diseases - etiology; Kidney Diseases - pathology; Kidney Glomerulus - metabolism; Kidneys; Male; Medical sciences; Nephrology. Urinary tract diseases; Protein Precursors - metabolism; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Cell Surface - metabolism; Renin - metabolism; Renin-Angiotensin System - physiology; Urinary system involvement in other diseases. Miscellaneous
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2005121278

Prorenin is activated without proteolysis by binding of prorenin receptor to the pentameric "handle region" (HR) of prorenin prosegment. It was hypothesized that such activation occurs in the kidneys of hypertensive rats and causes tissue renin-angiotensin system (RAS) activation and end-organ damage. Because the HR's binding to its binding protein made the adjacent tetrameric "gate region" (GR) accessible to its specific antibody, immunohistochemistry of the GR was performed to test the hypothesis. Methods also were devised specifically to inhibit the nonproteolytic activation by the decapeptide corresponding to the HR as a decoy. Immunohistochemistry of the GR demonstrated that the majority of nonproteolytically activated prorenin is present in podocytes of the kidneys from stroke-prone spontaneously hypertensive rats, in which activation of renal tissue RAS, proteinuria, and glomerulosclerosis occurred. Continuous subcutaneous administration of the HR decoy peptide completely inhibited both nonproteolytic activation of tissue prorenin and activation of tissue RAS without affecting circulating RAS or arterial pressure and significantly attenuated the development and progression of proteinuria and glomerulosclerosis. These studies clearly demonstrated that nonproteolytic activation of prorenin in glomeruli is critically involved in renal tissue RAS activation, leading to renal damage in hypertensive animals.