Regulation of glomerular TGF-beta expression in the contralateral kidney of two-kidney, one-clip hypertensive rats.
Previous studies have demonstrated that angiotensin II stimulates expression of transforming growth factor-beta (TGF-beta) in cultured renal cells. To investigate whether similar mechanisms are operative in vivo, glomerular TGF-beta mRNA expression was investigated in two-kidney, one-clip (2-K 1-C) hypertensive rats. Glomerular TGF-beta1 transcripts were elevated in the clipped kidney 6 d, but not 3 d, after surgery. Later, during the course of the disease (21 to 35 d), TGF-beta1 mRNA was upregulated in contralateral kidneys compared with sham-operated control kidneys. There was no difference in plasma TGF-beta1 levels between 2-K 1-C rats and controls. Treatment with the AT1 receptor antagonist losartan, as well as with triple therapy (hydralazine, reserpine, and hydrochlorothiazide), started 1 d after clipping, significantly reduced systolic BP in hypertensive rats at day 21 after clipping. Both treatments were equally effective in preventing the increase in glomerular TGF-beta1 mRNA and protein expression in the contralateral kidney at day 21. In a second set of experiments, interventional treatment with losartan or triple therapy, starting 14 d after surgery, was investigated. This treatment for 3 wk significantly reduced the increase in TGF-beta1 expression in the contralateral kidney. At day 35 after clipping, considerable glomerular damage and sclerosis were present, mainly in contralateral kidneys. Interventional treatment with losartan or triple therapy partly prevented this glomerular damage of the contralateral kidney. The data demonstrate that TGF-beta1 expression in the contralateral kidney in 2-K 1-C rats is regulated by the increase in systemic BP rather than by direct effects of angiotensin II.
Wolf
G
G
Department of Medicine, University of Hamburg, Germany.
Schneider
A
A
Wenzel
U
U
Helmchen
U
U
Stahl
R A
RA
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D004338:Drug Combinations; D006830:Hydralazine / Q000494:pharmacology; D006852:Hydrochlorothiazide / Q000494:pharmacology; D006978:Hypertension, Renovascular / Q000378:metabolism*; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012110:Reserpine / Q000494:pharmacology; D012598:Sclerosis; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D000959:Antihypertensive Agents; D004338:Drug Combinations; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D006852:Hydrochlorothiazide; D006830:Hydralazine; D012110:Reserpine; D019808:Losartan