Abstract
Renal ischemia–reperfusion injury (IRI) is less extensive in females than males in both animals and humans; however, this protection diminishes after menopause, suggesting that estrogen plays a pivotal role in IRI, but the underlying mechanism remains largely unknown. Our study found that 45 min of warm ischemia was sufficient to induce significant pathological changes without causing death in model animals. Compared with male rats, female rats exhibited less extensive apoptosis, kidney injury, and fibrosis; these effects were worsened in ovariectomized (OVX) rats and ameliorated upon estradiol (E2) supplementation. Furthermore, the levels of TGF-βRI, but not TGF-βRII or TGF-β1, were significantly increased in OVX rats, accompanied by phosphorylated SMAD2/3 activation. Interestingly, the alteration trend of the nuclear ERα level was opposite that of TGF-βRI. Furthermore, dual luciferase reporter and chromatin immunoprecipitation assays showed that ERα could bind to the promoter region of TGF-βRI and negatively regulate its mRNA expression. Moreover, an in vitro study using NRK-52E cells showed that ERα knockdown blocked E2-mediated protection, while TGF-βRI knockdown protected cells against hypoxic insult. The findings of this study suggest that renal IRI is closely related to the TGF-βRI-SMAD pathway in females and that E2 exert its protective effect via the ERα-mediated transcriptional inhibition of TGF-βRI expression.
Highlights
Renal ischemia–reperfusion injury (IRI), which occurs in 30%–50% of transplant patients, is a prevalent risk factor that contributes to acute kidney injury (AKI) and delayed graft function after kidney transplantation [1]
As there are no effective treatments for AKI, renal IRI is a major cause of morbidity and mortality [2] and accounts for 1% of hospital admissions, and its prevalence is approximately 7% in hospitalized patients [3]
45 min of renal ischemia followed by 24 h of reperfusion resulted in AKI, as reflected by marked increases in serum creatinine (Scr) levels and pathological changes in male and OVX rat kidneys as well as by increased TUNEL-positive staining, and these effects were reversed by E2 supplementation
Summary
Renal ischemia–reperfusion injury (IRI), which occurs in 30%–50% of transplant patients, is a prevalent risk factor that contributes to acute kidney injury (AKI) and delayed graft function after kidney transplantation [1]. Female animals are less likely to suffer from AKI than males [4], and estrogen protects renal tubular function after experimental ischemic injury [5]. Male animals, including humans, are more susceptible to IRI-induced kidney injury with worsened renal function than females [6]. A clinical study suggested that menopause contributes to more renal dysfunction in women due to estrogen withdrawal [10]. The application of estrogen-based postmenopausal hormone replacement therapy (HRT) has been suggested to ameliorate renal function in postmenopausal women and delay chronic kidney disease (CKD) progression [11]. Until now, the mechanisms responsible for the sex hormone-mediated differences in humans and animals with AKI have not been fully explored
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