Estrogen receptor β attenuates renal fibrosis by suppressing the transcriptional activity of Smad3

Renal fibrosis (RF) is a common pathway leading to chronic kidney disease (CKD), which lacks effective treatment. While estrogen receptor beta (ER beta) is known to be present in the kidney, its role in RF remains unclear. The present study aimed to investigate the role and underlying mechanism of ER beta during RF progression in patients and animal models with CKD. We found that ER beta was highly expressed in the proximal tubular epithelial cells (PTECs) in healthy kidneys but its expression was largely lost in patients with immunoglobin A nephropathy (IgAN) and in mice with unilateral ureter obstruction (UUO) and subtotal nephrectomy (5/6Nx). ER beta deficiency markedly exacerbated, whereas ER beta activation by WAY200070 and DPN attenuated RF in both UUO and 5/6Nx mouse models, suggesting a protective role of ER beta in RF. In addition, ER beta activation inhibited TGF-beta 1/Smad3 signaling, while loss of renal ER beta was associated with overactivation of the TGF-beta 1/Smad3 pathway. Furthermore, deletion or pharmacological inhibition of Smad3 prevented the loss of ER beta and RF. Mechanistically, activation of ER beta competitively inhibited the association of Smad3 with the Smad-binding element, thereby downregulating the transcription of the fibrosis-related genes without altering Smad3 phosphorylation in vivo and in vitro. In conclusion, ER beta exerts a renoprotective role in CKD by blocking the Smad3 signaling pathway. Thus, ER beta may represent as a promising therapeutic agent for RF.