Glomerulosclerosis and tubulointerstitial fibrosis are attenuated with 17beta-estradiol in the aging Dahl salt sensitive rat.
This study examined the effects of estrogen deficiency by ovariectomy (OVX) and 17beta-estradiol (E(2)) replacement (OVX+E(2)) on glomerulosclerosis and tubulointerstitial fibrosis and the mechanisms contributing to these changes, including expression of collagen type IV and laminin, transforming growth factor-beta (TGF-beta), 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 E(2) 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-beta (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). E(2) replacement opposed these effects (laminin, 229.9 +/- 6.2 AU; TGF-beta, 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+E(2), 0.28 +/- 0.01 mg/min per 100 g) and increase in BUN (Intact, 20.3 +/- 2.1; OVX, 32.6 +/- 5.1; OVX+E(2), 24.3 +/- 2.4 mg/dl). The authors conclude that E(2) is renoprotective in the aging DSS rat by attenuating glomerulosclerosis and tubulointerstitial fibrosis.
Maric
Christine
C
Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University Medical Center, 394 Building D, 4000 Reservoir Road NW, Washington, DC 20057, USA. cm255@georgetown.edu
Sandberg
Kathryn
K
Hinojosa-Laborde
Carmen
C
D000818:Animals; D001806:Blood Urea Nitrogen; D015153:Blotting, Western; D001835:Body Weight; D024141:Collagen Type IV / Q000378:metabolism; D003404:Creatinine / Q000378:metabolism; D004958:Estradiol / Q000097:blood / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000473:pathology*; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology*; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007672:Kidney Cortex / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D009929:Organ Size; D051381:Rats; D020303:Rats, Inbred Dahl; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014599:Uterus / Q000473:pathology
D024141:Collagen Type IV; D004967:Estrogens; D007797:Laminin; D016212:Transforming Growth Factor beta; D004958:Estradiol; D003404:Creatinine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9