Glomerulosclerosis and Tubulointerstitial Fibrosis are... : Journal of the American Society of Nephrology (original) (raw)

Pathophysiology of Renal Disease and Progression

Glomerulosclerosis and Tubulointerstitial Fibrosis are Attenuated with 17β-Estradiol in the Aging Dahl Salt Sensitive Rat

*Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University, Washington, DC; and †Department of Anesthesiology, University of Texas Health Science Center, San Antonio, Texas.

Correspondence to Dr. Christine Maric, Center for the Study of Sex Differences: in Health, Aging and Disease, Georgetown University Medical Center, 394 Bldg D, 4000 Reservoir road NW, Washington, DC, 20057. Phone: 202 687 5363; Fax: 202 687 7278; E-mail: [email protected]

Accepted March 26, 2004

Received December 29, 2003

Journal of the American Society of Nephrology 15(6):p 1546-1556, June 2004. | DOI: 10.1097/01.ASN.0000128219.65330.EA

Abstract

ABSTRACT. This study examined the effects of estrogen deficiency by ovariectomy (OVX) and 17β-estradiol (E2) replacement (OVX+E2) on glomerulosclerosis and tubulointerstitial fibrosis and the mechanisms contributing to these changes, including expression of collagen type IV and laminin, transforming growth factor-β (TGF-β), and activity of matrix metalloproteinases (MMP) in the kidneys of young (4 mo [4M]) and aged (12 mo [12M]) Dahl salt-sensitive (DSS) rats maintained on a low-salt (0.1% NaCl) diet. While normal renal morphology was observed in the 4M rats in all treatment groups, moderate to severe glomerulosclerosis (glomerulosclerotic index [GSI]: 4M, 0.22 ± 0.09 versus 12M, 1.43 ± 0.17; P < 0.001) and cortical tubulointerstitial fibrosis (CTIFI: 4M, 0 versus 12M, 57.1 ± 4.9; P < 0.01) was observed in the 12M rats. The severity of glomerulosclerosis and cortical tubulointerstitial fibrosis in the 12M group was augmented with OVX (GSI, 3.27 ± 0.34; CTIFI, 74.4 ± 9.2; P < 0.01 versus Intact at 12M) and attenuated with E2 replacement ([GSI], 1.09 ± 0.09; CTIFI, 49.2 ± 6.8). In the 12M animals, OVX was also associated with increased deposition and expression of laminin (Intact, 228.1 ± 6.7; OVX, 277.4 ± 9.6 AU; P < 0.01), increased expression of TGF-β (Intact, 85.0 ± 23.0; OVX, 178.0 ± 20.5 AU; P < 0.001), and decreased activity of cortical MMP-9 (Intact, 3.8 ± 0.8; OVX, 2.4 ± 0.6 AUC; P < 0.01). E2 replacement opposed these effects (laminin, 229.9 ± 6.2 AU; TGF-β, 101.3 ± 25.2 AU; MMP-9, 5.2 ± 0.2 AUC). The severity of the disease in the 12M rats correlated with a modest decrease in creatinine clearance (Intact, 0.26 ± 0.01; OVX, 0.22 ± 0.01; OVX+E2, 0.28 ± 0.01 mg/min per 100 g) and increase in BUN (Intact, 20.3 ± 2.1; OVX, 32.6 ± 5.1; OVX+E2, 24.3 ± 2.4 mg/dl). The authors conclude that E2 is renoprotective in the aging DSS rat by attenuating glomerulosclerosis and tubulointerstitial fibrosis.