Liu Suwen, Yang Yunwen, Li Qian, Yu Lichun, Zong Zihan, Zang Ruixian, Ji Wentao, Sun Shuzhen
Department of Pediatric Nephrology and Rheumatism and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Department of Pediatric Nephrology and Rheumatism and Immunology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.
Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing 210008, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
Biochim Biophys Acta Mol Basis Dis. 2025 Mar;1871(3):167660. doi: 10.1016/j.bbadis.2025.167660. Epub 2025 Jan 7.
Renal interstitial fibrosis is the main factor determining chronic kidney disease (CKD) progression, and renal tubular epithelial cells are the key drivers of this pathological process. Herein, we revealed significantly increased ubiquitin-specific peptidase 10 (USP10) expression in the kidney tissues of both patients with CKD and mice induced by unilateral ureteral obstruction, as well as in transforming growth factor-beta 1 (TGFβ1)-induced renal tubular epithelial cells. In vivo, treatment with the USP10 small molecule inhibitor Spautin-1, which inhibits its deubiquitinating activity, weakened renal interstitial fibrosis progression and alleviated the subsequent inflammatory response and oxidative stress in male mice. In vitro, knocking down USP10 or inhibiting its deubiquitinating activity through Spautin-1 significantly reduced fibronectin expression and ameliorated TGFβ1-induced renal tubular epithelial cell dedifferentiation. Additionally, our results revealed that USP10 directly binds to P53 and removes the K48-linked polyubiquitin chains from P53, thereby affecting its ubiquitination, stability, and nuclear translocation, which subsequently leads to the upregulation of P21 and promotes fibrotic gene expression in injured renal tubular epithelial cells, ultimately exacerbating renal interstitial fibrosis. In conclusion, USP10 is inhibited through the P53 signaling pathway to alleviate the progression of renal interstitial fibrosis and serve as a potential target for treating CKD.
肾间质纤维化是决定慢性肾脏病（CKD）进展的主要因素，而肾小管上皮细胞是这一病理过程的关键驱动因素。在此，我们发现CKD患者和单侧输尿管梗阻诱导的小鼠的肾组织中，以及转化生长因子-β1（TGFβ1）诱导的肾小管上皮细胞中，泛素特异性肽酶10（USP10）的表达显著增加。在体内，用抑制其去泛素化活性的USP10小分子抑制剂Spautin-1治疗，可减弱雄性小鼠肾间质纤维化的进展，并减轻随后的炎症反应和氧化应激。在体外，敲低USP10或通过Spautin-1抑制其去泛素化活性，可显著降低纤连蛋白的表达，并改善TGFβ1诱导的肾小管上皮细胞去分化。此外，我们的结果表明，USP10直接与P53结合，并去除P53上K48连接的多聚泛素链，从而影响其泛素化、稳定性和核转位，随后导致P21上调，并促进损伤的肾小管上皮细胞中纤维化基因的表达，最终加剧肾间质纤维化。总之，通过P53信号通路抑制USP10可减轻肾间质纤维化的进展，并作为治疗CKD的潜在靶点。
