Department of Chemistry and Molecular Biology and.
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
JCI Insight. 2020 Dec 17;5(24):140483. doi: 10.1172/jci.insight.140483.
Diabetic kidney disease (DKD) is the most common cause of severe renal disease worldwide and the single strongest predictor of mortality in diabetes patients. Kidney steatosis has emerged as a critical trigger in the pathogenesis of DKD; however, the molecular mechanism of renal lipotoxicity remains largely unknown. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase 25 (STK25) as a critical regulator of ectopic lipid storage in several metabolic organs prone to diabetic damage. Here, we demonstrate that overexpression of STK25 aggravates renal lipid accumulation and exacerbates structural and functional kidney injury in a mouse model of DKD. Reciprocally, inhibiting STK25 signaling in mice ameliorates diet-induced renal steatosis and alleviates the development of DKD-associated pathologies. Furthermore, we find that STK25 silencing in human kidney cells protects against lipid deposition, as well as oxidative and endoplasmic reticulum stress. Together, our results suggest that STK25 regulates a critical node governing susceptibility to renal lipotoxicity and that STK25 antagonism could mitigate DKD progression.
糖尿病肾病（DKD）是全球范围内导致严重肾脏疾病的最常见原因，也是糖尿病患者死亡的单一最强预测因素。肾脏脂肪变性已成为 DKD 发病机制中的关键触发因素；然而，肾脂毒性的分子机制在很大程度上仍不清楚。我们最近在遗传小鼠模型、人类细胞系和特征明确的患者队列中的研究表明，丝氨酸/苏氨酸蛋白激酶 25（STK25）是几种易发生糖尿病损伤的代谢器官中异位脂质储存的关键调节因子。在这里，我们证明 STK25 的过表达会加重 DKD 小鼠模型中的肾脏脂质积累，并加剧结构和功能肾脏损伤。相反，在小鼠中抑制 STK25 信号转导可改善饮食诱导的肾脏脂肪变性，并减轻与 DKD 相关的病理发展。此外，我们发现人肾细胞中的 STK25 沉默可防止脂质沉积以及氧化应激和内质网应激。总之，我们的结果表明 STK25 调节了一个控制对肾脂毒性易感性的关键节点，而 STK25 拮抗作用可能减轻 DKD 的进展。
