Gene expression in rats with renal disease treated with the angiotensin II receptor antagonist, eprosartan.
The role of ANG II on renal and cardiac gene expression of matrix proteins was studied in rats with progressive renal disease. Induction of renal failure by five-sixths nephrectomy of Sprague-Dawley rats resulted in hypertension (163 +/- 19 vs. control pressures of 108 +/- 6 mmHg), proteinuria (83 +/- 47 vs. 14 +/- 2 mg/day), and increased renal expression of fibronectin, thrombospondin, collagen I and III, transforming growth factor-beta (TGF-beta), and plasminogen activator inhibitor-1 (PAI-1) mRNA. Treatment with the ANG II receptor antagonist, eprosartan (60 mg. kg(-1).day(-1)), lowered blood pressure (95 +/- 5 mmHg) and proteinuria (19 +/- 8 mg/d) and abrogated the increased TGF-beta, fibronectin, thrombospondin, collagens I and III, and PAI-1 mRNA expression. An increase in left ventricular weight was observed in five-sixths nephrectomized rats (0.13 +/- 0.01 vs. 0.08 +/- 0.01 g/100 g body wt), a response that was inhibited by eprosartan treatment (0.10 +/- 0.01 g/100 g). Left ventricular expression of TGF-beta and fibronectin was also increased in rats with renal disease; however, the small decreases in expression observed in eprosartan-treated rats did not reach statistical significance. These data suggest that eprosartan may be beneficial in progressive renal disease and that the mechanism of action includes inhibition of cytokine production in addition to antihypertensive activity.
Wong
V Y
VY
Department of Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Laping
N J
NJ
Contino
L C
LC
Olson
B A
BA
Grygielko
E
E
Brooks
D P
DP
D000179:Acrylates / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D007093:Imidazoles / Q000494:pharmacology*; D007674:Kidney Diseases / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D009392:Nephrectomy; D011507:Proteinuria / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes
D000179:Acrylates; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; D013876:Thiophenes; C068373:eprosartan