2-Hydroxyestradiol Attenuates Renal Disease in Chronic Puromycin Aminonucleoside Nephropathy

Abstract

Abstract. 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 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 mol/L; P Ͻ 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 mol/L) were not blocked by ICI182780 (50 mol/L), an estrogen receptor antagonist. In vivo, chronic administration of PAN (75 mg/kg ϩ 5 ϫ 20 mg/kg) over 12 wk induced severe chronic renal disease.Chronic treatment with 2-OHE significantly (P Ͻ 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-␤ (TGF-␤) 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 ϩ cells). 2-OHE had no effects on renal tubular cell TGF-␤, 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.Recent data indicate that the rate of progression of chronic renal disease (CRD) of various etiologies is more rapid in men than in women and is independent of BP or serum cholesterol levels (1,2). Accelerated arteriosclerosis and excessive rate of cardiovascular morbidity and mortality characterize CRD (3), and, similarly to cardiovascular disease, the incidence and prevalence of CRD is higher in men than in women (4). Although the involvement of genetic factors, environment, and androgens should not be neglected, the resistance of kidneys in women to the progression of renal disease is most frequently attributed to estrogens (2).Our recent studies suggest that several of th...

2-Hydroxyestradiol Is a Prodrug of 2-Methoxyestradiol

“…The potential use of 2MEOE is currently being evaluated in phase I and phase II clinical trials for the treatment of multiple types of cancer, including breast cancer, advanced refractory metastatic breast cancer, and hormone-refractory prostate cancer (Lakhani et al, 2003). In addition to being a potent anticarcinogenic agent, animal studies provide evidence that 2MEOE may effectively protect against proliferative disorders associated with cardiovascular disease, renal disease, and obesity (Tofovic et al, 2001(Tofovic et al, , 2002.…”

“…Our in vivo work demonstrates that 2OHE attenuates the development of obesity, the metabolic syndrome, and vascular and renal dysfunction in obese ZSF1 rats (Tofovic et al, 2001). Moreover, our more recent studies indicate that 2OHE protects against puromycin aminonucleoside-induced nephropathy (Tofovic et al, 2002), monocrotaline-induced pulmonary hypertension (Tofovic et al, 2003b), and angiotensin II-induced renal and cardiovascular injury (Tofovic et al, 2003a).…”

“…Our in vivo work demonstrates that 2OHE attenuates the development of obesity, the metabolic syndrome, and vascular and renal dysfunction in obese ZSF1 rats (Tofovic et al, 2001). Moreover, our more recent studies indicate that 2OHE protects against puromycin aminonucleoside-induced nephropathy (Tofovic et al, 2002), monocrotaline-induced pulmonary hypertension (Tofovic et al, 2003b), and angiotensin II-induced renal and cardiovascular injury (Tofovic et al, 2003a).Although the aforementioned in vivo studies were conducted with 2OHE, in point-of-fact 2OHE is readily oxidized and is therefore a poor candidate for drug development. 2-Methoxyestradiol (2MEOE), on the other hand, is less susceptible to oxidation, and in vitro evidence suggests that most of the cellular effects of 2OHE are mediated by 2MEOE, a metabolite of 2OHE that is devoid of estrogenic activity.…”

Estrone/17β‐estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritis

“…In chronic antibiotic-induced nephropathy in rats, 2OH-17␤-estradiol improved glomerular filtration, reduced proteinuria, and attenuated elevated blood pressure (11). The results of a case-control analysis using pretreatment urine samples suggested that a lower ratio of 2-hydroxyestrogen to 16-hydroxyestrogen was associated with an increased risk of premenopausal and postmenopausal breast cancer diagnosis among Chinese women (12).…”

Characterization of liver changes in ZSF1 rats, an animal model of metabolic syndrome

“…These animals are generated by crossing non-hypertensive lean female Zucker diabetic fatty rats (ZDF, +/fa) with lean spontaneously hypertensive HF prone male rats (SHHF/Mcc, +/facp), which share a common genetic background with Wistar Kyoto rats (used as control) and derive from spontaneously multifactorial hypertensive rats. Both lean and obese ZSF1 animals inherit a hypertensive gene from the spontaneously hypertensive rat strain and have high blood pressure (23)(24)(25)(26). With regard to metabolism, ZSF1 animals develop obesity, abdominal adiposity, insulin resistance, oral glucose intolerance, hyperglycaemia and glycosuria, consistent with a type II diabetes mellitus phenotype (27).…”