Regression of Renal Vascular and Glomerular Fibrosis: Role... : Journal of the American Society of Nephrology (original) (raw)

Hemodynamics, Hypertension and Vascular Regulation

Role of Angiotensin II Receptor Antagonism and Matrix Metalloproteinases

Boffa, Jean-Jacques*; Lu, Ying*; Placier, Sandrine*; Stefanski, Adam*; Dussaule, Jean-Claude†; Chatziantoniou, Christos*

*INSERM U.489, Ho[Combining Circumflex Accent]pital Tenon, Paris; and †AP-HP, Laboratoire de Physiologie, UFR St Antoine, Paris, France.

Correspondence to Dr. Christos Chatziantoniou, INSERM U.489, Ho[Combining Circumflex Accent]pital Tenon, 75020 Paris, France. Phone: 331-56-01-66-58; Fax: 331-43-64-54-48;

Accepted January 17, 2003

Received April 02, 2002

Journal of the American Society of Nephrology 14(5):p 1132-1144, May 2003. | DOI: 10.1097/01.ASN.0000060574.38107.3B

Abstract

ABSTRACT. Renal fibrosis is one of the major complications associated with the development of hypertension. The objective of the present study was to determine whether and by which mechanisms treatment with AT1 receptor antagonists makes possible the regression of renal vascular and glomerular fibrosis. Experiments were performed in the hypertensive model of nitric oxide (NO) deficiency in rats. After 4 wk of hypertension, mortality rates averaged 20%; the surviving animals displayed a decline of renal function (urine protein/creatinine, 1.89 ± 0.63 versus 0.24 ± 0.03 mg/mmol; creatininemia, 110 ± 14 versus 38 ± 2 mmol/L in hypertensive animals and control, respectively; P < 0.01) and an exaggerated gene and protein expression of TGF-β, collagen I, and collagen IV (P < 0.001) within the renal vasculature associated with the development of glomerulosclerosis (sclerotic index, 2.26 ± 0.29 versus 0.12 ± 0.04; P < 0.001). In addition, activities of matrix metalloproteinases 2 and 9 were increased twofold in renal vessels and glomeruli (P < 0.01). Afterwards, losartan, an antagonist of angiotensin receptor type I, or hydralazine were administered in subgroups of hypertensive animals. After 1 wk of angiotensin II antagonism, collagen I, collagen IV, and TGF-β gene and protein expressions were decreased and glomerulosclerosis was less marked (sclerotic index 1.04 ± 0.45), whereas activities of metalloproteinases remained twofold higher than controls (P < 0.01). Hydralazine failed to improve renal function despite a similar degree of systolic pressure decrease. After 4 wk of losartan, the renal functional and histologic parameters were completely normalized, whereas they remained damaged in the hypertensive animals in which the mortality rate reached 85%. These data suggest that the progression of renal vascular fibrosis is a reversible process, at least in the NO deficiency model. The mechanism of the regression appears to be dual: inhibition of collagen synthesis due to AT1 receptor antagonism and activation of metalloproteinases that is probably associated with the degree of fibrosis independently of AT1 blockade. E-mail: [email protected]