REGULATION OF GLOMERULAR TGF-BETA EXPRESSION IN THE CONTRALATERAL KIDNEY OF 2-KIDNEY, ONE-CLIP HYPERTENSIVE RATS

Previous studies have demonstrated that angiotensin II stimulates expr ession of transforming growth factor-beta (TGF-beta) in cultured renal cells. To investigate whether similar mechanisms are operative in viv o, glomerular TGF-beta mRNA expression was investigated in two-kidney, one-clip (2-K 1-C) hypertensive rats. Glomerular TGF-beta(1) transcri pts were elevated in the clipped kidney 6 d, but not 3 d, after surger y. Later, during the course of the disease (21 to 35 d), TGF-beta(1) m RNA was upregulated in contralateral kidneys compared with sham-operat ed control kidneys. There was no difference in plasma TGF-beta(1) leve ls between 2-K 1-C rats and controls. Treatment with the AT(1) recepto r antagonist losartan, as well as with triple therapy (hydralazine, re serpine, and hydrochlorothiazide), started 1 d after clipping, signifi cantly reduced systolic BP in hypertensive rats at day 21 after clippi ng. Both treatments were equally effective in preventing the increase in glomerular TGF-beta(1) mRNA and protein expression in the contralat eral 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-beta(1) expression in the contralateral kidney. At day 35 after clipping, considerable glomerular damage and sclerosis were present, mainly in contralateral kidneys. Interventional treatment wit h losartan or triple therapy partly prevented this glomerular damage o f the contralateral kidney. The data demonstrate that TGF-beta(1) expr ession 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.