2-Hydroxyestradiol attenuates renal disease in chronic puromycin aminonucleoside nephropathy.
It has been previously shown that 2-hydroxyestradiol (2-OHE) attenuates the development of renal disease in genetic nephropathy associated with obesity and the metabolic syndrome. The purpose of this study was to test the hypothesis that 2-OHE, irrespective of its effects on metabolic status and/or obesity, exerts direct renoprotective effects in vivo. First, the effects of increasing doses of 2-OHE on mesangial cell growth, proliferation, and collagen synthesis in isolated rat glomerular mesangial cells were evaluated in vitro. Second, the effects of 12-wk administration of 2-OHE (10 micro g/h per kg) on renal function and structure in chronic puromycin aminonucleoside (PAN)-induced nephropathy in rats were evaluated in vivo. 2-OHE concentration-dependently (0.001 to 1 micro mol/L; P < 0.001) inhibited serum (2.5%)-induced cell growth ((3)H-thymidine incorporation), collagen synthesis ((3)H-proline incorporation), and cell proliferation (cell number). Importantly, the inhibitory effects of 2-OHE (0.1 micro mol/L) were not blocked by ICI182780 (50 micro mol/L), an estrogen receptor antagonist. In vivo, chronic administration of PAN (75 mg/kg + 5 x 20 mg/kg) over 12 wk induced severe chronic renal disease. Chronic treatment with 2-OHE significantly (P < 0.05) attenuated PAN-induced decrease in glomerular filtration, reduced proteinuria, and the elevated BP, and it had no effect on PAN-induced increase in plasma cholesterol and triglycerides levels. 2-OHE had no effects on plasma testosterone levels in male nephropathic animals. Immunohistochemical staining for collagen IV and proliferating cell nuclear antigen (PCNA) in glomeruli and transforming growth factor-beta (TGF-beta) in renal tubular cells were significantly higher in PAN nephropatic rats versus control animals with intact kidneys. PAN also markedly increased glomerular and interstitial macrophage infiltration (ED1(+) cells). 2-OHE had no effects on renal tubular cell TGF-beta, but it significantly reduced glomerular PCNA and collagen IV and glomerular and interstitial macrophage infiltration. In summary, this study provides the first evidence that 2-OHE exerts direct renoprotective effects in vivo. These effects are mediated by estrogen receptor-independent mechanisms and are due, at least in part, to the inhibition of some of the key proliferative mechanisms involved in glomerular remodeling and sclerosis.
Tofovic
Stevan P
SP
Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA. tofovic@msx.dept-med.pitt.edu
Dubey
Raghvendra
R
Salah
Eman M
EM
Jackson
Edwin K
EK
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002908:Chronic Disease; D024141:Collagen Type IV / Q000378:metabolism; D019610:Cytoprotection; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007150:Immunohistochemistry; D007676:Kidney Failure, Chronic / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011507:Proteinuria / Q000652:urine; D011692:Puromycin Aminonucleoside; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D012016:Reference Values; D016212:Transforming Growth Factor beta / Q000378:metabolism
D024141:Collagen Type IV; D018809:Proliferating Cell Nuclear Antigen; D011960:Receptors, Estrogen; D016212:Transforming Growth Factor beta; D004958:Estradiol; D011692:Puromycin Aminonucleoside; C001390:2-hydroxyestradiol