Hypoxia promotes renal interstitial fibrosis by activating the HIF-1α-SOX9 signaling pathway

This is the authors' abstract. We don't add key points for this paper.

Renal interstitial fibrosis (RIF) represents the most common pathological hallmark of various renal diseases progressing to chronic kidney disease (CKD), with hypoxia serving as a critical microenvironmental trigger in this process. Hypoxia-inducible factor-1α (HIF-1α) is a major regulator of cellular adaptation to low oxygen, yet its precise role in RIF remains incompletely defined. In this study, we observed upregulated expression of both HIF-1α and sex-determining region Y-box 9 (SOX9) in kidney tissues from patients with CKD and in adenine-induced CKD rat models. To investigate the underlying mechanism, fibrosis was examined in NRK-52E renal tubular epithelial cells cultured under hypoxic conditions (1% O2). Hypoxic exposure increased the expression of HIF-1α and SOX9, along with the induction of mesenchymal markers alpha-smooth muscle actin and collagen I. Pharmacological inhibition of HIF-1α with 2-methoxyestradiol decreased SOX9 expression and attenuated the hypoxic induction of mesenchymal markers. Conversely, stabilization of HIF-1α with deferoxamine under normoxic conditions elevated SOX9 levels and promoted fibrosis. Furthermore, siRNA-mediated knockdown of SOX9 inhibited hypoxia-induced fibrosis in NRK-52E cells. Collectively, our findings indicate that hypoxia regulates SOX9 expression through HIF-1α activation, which in turn promotes fibrosis in renal tubular epithelial cells.