title: Contribution of nonproteolytically activated prorenin in glomeruli to hypertensive renal damage.
abstract: 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.
authors.affiliation: Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. atzichi@sc.itc.keio.ac.jp
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Ichihara
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kaneshiro
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takemitsu
authors.forename: Mariyo
authors.initials: M
authors.lastname: Sakoda
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawachi
authors.forename: Fujio
authors.initials: F
authors.lastname: Shimizu
authors.forename: Tadashi
authors.initials: T
authors.lastname: Inagami
mesh_terms: D000818:Animals; D024141:Collagen Type IV / Q000096:biosynthesis; D004789:Enzyme Activation; D006973:Hypertension / Q000503:physiopathology*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism*; D008297:Male; D011498:Protein Precursors / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011956:Receptors, Cell Surface / Q000378:metabolism; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D000093342:Prorenin Receptor
chemical_list: D024141:Collagen Type IV; D011498:Protein Precursors; D011956:Receptors, Cell Surface; D012083:Renin; D000093342:Prorenin Receptor