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Slowly Progressive, Angiotensin II–Independent Glomerulosclerosis in Human (Pro)renin Receptor–Transgenic Rats

Yuki Kaneshiro^*, Atsuhiro Ichihara^*, Mariyo Sakoda^*, Tomoko Takemitsu^*, A.H.M. Nurun Nabi, M. Nasir Uddin, Tsutomu Nakagawa, Akira Nishiyama, Fumiaki Suzuki^,, Tadashi Inagami^|| and Hiroshi Itoh^*

^* Department of Internal Medicine, Keio University School of Medicine, Tokyo, United Graduate School of Agricultural Science and Faculty of Applied Biological Sciences, Gifu University, Gifu, and Department of Pharmacology, Kagawa University School of Medicine, Kagawa, Japan; and ^|| Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee

Address correspondence to: Dr. Atsuhiro Ichihara, Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. Phone: +81-3-5363-3796; Fax: +81-3-5363-3980; E-mail: atzichi{at}sc.itc.keio.ac.jp

Received for publication September 28, 2006. Accepted for publication March 23, 2007.

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-1 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-1 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-1 expression.

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