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, Hiroshi Itoh

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Abstract

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-β1 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-β1 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-β1 expression.

Original languageEnglish
Pages (from-to)1789-1795
Number of pages7
JournalJournal of the American Society of Nephrology
Volume18
Issue number6
DOIs
Publication statusPublished - 2007 Jun

ASJC Scopus subject areas

  • Nephrology

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    Kaneshiro, Y., Ichihara, A., Sakoda, M., Takemitsu, T., Nabi, A. H. M. N., Uddin, M. N., Nakagawa, T., Nishiyama, A., Suzuki, F., Inagami, T., & Itoh, H. (2007). Slowly progressive, angiotensin II-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats. Journal of the American Society of Nephrology, 18(6), 1789-1795. https://doi.org/10.1681/ASN.2006091062