Slowly progressive, angiotensin II-Independent glomerulosclerosis in human (Pro)renin receptor-transgenic rats

• Published in: Journal of the American Society of Nephrology Vol. 18; no. 6; pp. 1789 - 1795
• Main Authors: KANESHIRO, Yuki, ICHIHARA, Atsuhiro, ITOH, Hiroshi, SAKODA, Mariyo, TAKEMITSU, Tomoko, NURUN NABI, A. H. M, NASIR UDDIN, M, NAKAGAWA, Tsutomu, NISHIYAMA, Akira, SUZUKI, Fumiaki, INAGAMI, Tadashi
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01-06-2007
• Subjects: Age Factors; Angiotensin I - metabolism; Angiotensin II - metabolism; Animals; Animals, Genetically Modified; Biological and medical sciences; Cercopithecus aethiops; COS Cells; Disease Progression; Glomerulonephritis; Glomerulosclerosis, Focal Segmental - metabolism; Glomerulosclerosis, Focal Segmental - pathology; Glomerulosclerosis, Focal Segmental - physiopathology; Humans; MAP Kinase Signaling System - physiology; Medical sciences; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Proteinuria - metabolism; Proteinuria - pathology; Proteinuria - physiopathology; Rats; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Transforming Growth Factor beta1 - metabolism; Glomerulonephritis; Kidney disease; Human; Glomerulosclerosis; Nephrology; Urinary system disease; Rat; Enzyme; Peptide hormone; Rodentia; Urology; Progressive; Peptidases; Octapeptide; Renin angiotensin system; Vertebrata; Mammalia; Renin; Animal; Hydrolases; Aspartic endopeptidases; Angiotensin II; Biological receptor
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2006091062

For defining the pathogenic effects of the (pro)renin receptor-transgenic rat, strains that overexpressed the human receptor were generated. Although transgenic rats were normotensive and euglycemic and had a renal angiotensin II (AngII) level that was comparable to that of wild-type rats, transgenic rats developed proteinuria with aging and significant glomerulosclerosis at 28 wk of age. In kidneys of 28-wk-old transgenic rats, mitogen-activated protein kinases (MAPK) were activated without recognizable tyrosine phosphorylation of the EGF receptor, and expression of TGF-beta1 was enhanced. In vivo infusion of the (pro)renin receptor blocker peptide (formerly handle region decoy peptide) significantly inhibited the development of glomerulosclerosis, proteinuria, MAPK activation, and TGF-beta1 expression in the kidneys, but the angiotensin-converting enzyme inhibitor did not attenuate these changes despite a significant decrease in the renal AngII level. In addition, recombinant rat prorenin stimulated MAPK activation in the human receptor-expressed cultured cells, but human receptor was unable to evoke the enzyme activity of rat prorenin. Thus, human (pro)renin receptor elicits slowly progressive nephropathy by AngII-independent MAPK activation in rats. This study clearly provided in vivo evidence for the AngII-independent MAPK activation by human (pro)renin receptor and induction of glomerulosclerosis with increased TGF-beta1 expression.