Slowly progressive, angiotensin II-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats.
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.
Kaneshiro
Yuki
Y
Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Ichihara
Atsuhiro
A
Sakoda
Mariyo
M
Takemitsu
Tomoko
T
Nabi
A H M Nurun
AH
Uddin
M Nasir
MN
Nakagawa
Tsutomu
T
Nishiyama
Akira
A
Suzuki
Fumiaki
F
Inagami
Tadashi
T
Itoh
Hiroshi
H
D000367:Age Factors; D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D019556:COS Cells; D002522:Chlorocebus aethiops; D018450:Disease Progression; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000093342:Prorenin Receptor
D011956:Receptors, Cell Surface; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D000803:Angiotensin I; D000093342:Prorenin Receptor