Estradiol Ameliorates Acute Kidney Ischemia-Reperfusion Injury by Inhibiting the TGF-βRI-SMAD Pathway

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.

Post COVID-19 hyperinflammatory acute kidney injury and background ovarian insufficiency: Renal functional restoration after combined angiotensin-converting enzyme inhibitor with estrogen replacement

“…Females with COVID-19 generally have better prognoses than males-a protective effect attributed to estrogen-but this advantage disappears after menopause [18,19]. Recent research has found an androgen-sensitive transmembrane serine protease facilitates SARS-CoV-2 access to cells, so women with relative androgen surplus might be at increased risk of COVID-19 infection by this pathway [20].…”

Evaluation of pharmacokinetics and safety of a long-term estradiol-releasing stent in rat uterine

“…The mechanism of E2 inhibiting TGF-β signaling is most likely through promoting Smad 2/3 degradation [ 27 ]. E2 protection against ischemia-reperfusion injury-induced renal fibrosis is also exerted by inhibition of TGF-β type I receptor-SMAD pathway [ 28 ].…”

Gender and Renal Insufficiency: Opportunities for Their Therapeutic Management?

“…However, the role of TGF-β1 in renal AKI is still unclear. Some researchers have found that TGF-β1 plays a protective role in acute injury, while others have shown that TGF-β1 accumulation induces AKI [ 82 , 83 , 84 ]. In our opinion, considering the evidence described so far, the protective role of female sex hormones in limiting acute kidney damage and limiting the inflammatory and fibrotic activity of the damaged parenchyma seems clear.…”