Role of aberrant iron homeostasis in the upregulation of transforming growth factor-beta1 in the kidney of angiotensin II-induced hypertensive rats.
We have previously shown that abnormal iron metabolism might be one underlying mechanism of the renal damage observed in the angiotensin II-infused rat. Transforming growth factor-beta1 (TGF-beta1) is known to play a crucial role in the development of renal damage induced by activation of the renin-angiotensin-aldosterone system. The purpose of the present study was to examine the effects of an iron chelator and a free radical scavenger on the angiotensin II-induced upregulation of TGF-beta1 in the kidney. Rats were given angiotensin II (0.7 mg/kg/day) via osmotic minipumps for 7 days. The expressions of the mRNAs of TGF-beta1 and collagen types I and IV were significantly increased in response to angiotensin II treatment. Histologic analysis showed that TGF-beta1 expression was upregulated mainly in tubular epithelial cells, and occasionally in glomerular and perivascular cells, some of which were identified as monocytes and/or macrophages. Although tubular cells that overexpressed TGF-beta1 did not contain iron particles, angiotensin II-induced TGF-beta1 upregulation was suppressed by the iron chelator and the free radical scavenger. The free radical scavenger also suppressed angiotensin II-induced upregulation of heme oxygenase-1, an oxidative-stress sensitive gene. By contrast, administration of iron dextran to rats induced upregulation of TGF-beta1 mRNA. Collectively, these data suggest that the renal iron overload and presumed subsequent increase in oxidative stress play a role in angiotensin II-induced upregulation of the mRNAs of TGF-beta1 and collagen types I and IV in the kidney.
Saito
Kan
K
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Japan.
Ishizaka
Nobukazu
N
Aizawa
Toru
T
Sata
Masataka
M
Iso-O
Naoyuki
N
Noiri
Eisei
E
Ohno
Minoru
M
Nagai
Ryozo
R
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D003094:Collagen / Q000235:genetics; D005293:Ferritins / Q000378:metabolism; D005355:Fibrosis; D016166:Free Radical Scavengers / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D006706:Homeostasis / Q000502:physiology; D006977:Hypertension, Renal / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D019190:Iron Overload / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014662:Vasoconstrictor Agents; D013481:Superoxides; D000804:Angiotensin II; D003094:Collagen; D005293:Ferritins; D007501:Iron; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1