Transforming growth factor beta1-induced glomerulopathy is prevented by 17beta-estradiol supplementation.
Transforming growth factor beta1 (TGF-beta1) affects extracellular matrix (ECM) accumulation. It plays a role in the thickening of the peripheral basement membrane (PBM) and expansion of the mesangium in several renal diseases. The beneficial influence of female gender on the progression of chronic renal diseases may be explained by a favorable effect of estrogen on ECM homeostasis. Interactions between TGF-beta1 and estrogen have been investigated in mesangial cell cultures. However, it is unknown if TGF-beta1-induced glomerulopathy in vivo is influenced by exogenous estrogen. Thus, the aim of the present experiment was to explore whether estrogen prevents the development of TGF-beta1-induced glomerular disease in transgenic mice expressing active TGF-beta1 under control of the Ren-1c promoter. Mice were treated from 3 weeks to 6 weeks of age with 17beta-estradiol release pellets (5-10 microg/kg body weight per day). At the age of 6 weeks, all investigated animals were sacrificed for estimation of PBM thickness, the mesangium per glomerulus [Vv(mes/glom)], the mesangial matrix per glomerulus [Vv(matrix/glom)] and the PBM per glomerulus [Vv(PBM/glom)] using electron microscopy and stereological methods. Furthermore, the total collagen content was determined. We found that TGF-beta1-induced alterations in Vv(mes/glom), Vv(matrix/glom) and Vv(PBM/glom) were prevented in mice exposed to exogenous 17beta-estradiol. In addition, the interstitial fibrosis that develops in TGF-beta1 transgenic mice was attenuated by administration of 17beta-estradiol. In conclusion, estrogen may oppress TGF-beta1-mediated kidney diseases and, thereby, contribute to the protracted development of end-stage renal disease in pre-menopausal women.
Birch Nielsen
Camilla
C
The Research Laboratory for Biochemical Pathology, The Institute of Experimental Clinical Research, Aarhus University, Aarhus Kommunehospital, 44-Noerrebrogade, 8000 Aarhus C, Aarhus, Denmark.
Krag
Søren
S
ØSterby
Ruth
R
Flyvbjerg
Allan
A
Nyengaard
Jens
J
Forman
Axel
A
Wogensen
Lise
L
D000818:Animals; D001485:Basement Membrane / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D004958:Estradiol / Q000097:blood / Q000627:therapeutic use*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005921:Glomerulonephritis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D006909:Hydroxyproline / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007676:Kidney Failure, Chronic; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012083:Renin / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D019076:Transgenes
C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004958:Estradiol; D012083:Renin; D006909:Hydroxyproline