CCDC92 deficiency ameliorates podocyte lipotoxicity in diabetic kidney disease
CCDC92 deficiency ameliorates podocyte lipotoxicity in diabetic kidney disease
复制标题
DOI：
10.1016/j.metabol.2023.155724
复制
发表时间：
2023-11-18
影响因子：
9.8
通讯作者：
Yi，Fan
中科院分区：
文献类型：
--
作者：
Zuo，Fuwen;Wang，Youzhao;Yi，Fan
背景和目的细胞损伤被认为是糖尿病肾病（DKD）最重要的早期事件。最近的研究结果为脂质和脂质调节蛋白作为足细胞功能在健康和肾脏疾病中的关键决定因素的作用提供了新的见解。CCDC92是卷曲卷曲结构域蛋白家族的新成员，被认为与脂质代谢、冠心病和2型糖尿病有关。然而，CCDC92在肾脏中的表达模式和作用尚不清楚。本研究旨在阐明CCDC92在DKD发病机制中的作用。方法对病理诊断为轻度DKD （II类，n = 6）、中度DKD （III类，n = 6）、重度DKD （IV类，n = 6）和对照样本（n = 12）的不同类型DKD患者切片进行CCDC92表达水平和脂质积累检测。为了阐明CCDC92在足细胞特异性CCDC92敲除背景下的作用，我们建立了两种糖尿病小鼠模型（db/dband HFD/STZ）。结果DKD患者肾活检切片中CCDC92水平升高，与肾小球eGFR和脂质积累相关。在动物实验中，CCDC92也在两种独立的糖尿病模型肾脏中被诱导，尤其是足细胞。足细胞特异性缺失ccdc92可改善糖尿病足细胞损伤和异位脂质沉积。机械上，CCDC92促进足细胞脂毒性，至少部分通过ABCA1信号介导的脂质稳态。结论我们的研究表明，CCDC92作为一种新的脂质稳态调节因子，促进DKD足细胞损伤，提示CCDC92可能是DKD足细胞损伤的潜在生物标志物，靶向CCDC92可能是DKD患者有效的创新治疗策略。
Background and aimsPodocyte injury is considered as the most important early event contributing to diabetic kidney disease (DKD). Recent findings provide new insights into the roles of lipids and lipid-modulating proteins as key determinants of podocyte function in health and kidney disease. CCDC92, a novel member of coiled-coil domain-containing protein family, was indicated relevant to lipid metabolism, coronary heart disease and type 2 diabetes. However, the expression pattern and role of CCDC92 in the kidney is not clear. This study was designed to elucidate the contribution of CCDC92 in the pathogenesis of DKD.MethodsSections with a pathological diagnosis of different classes of DKD, including subjects with mild DKD (class II, n = 6), subjects with moderate DKD (class III, n = 6) or subjects with severe DKD (class IV, n = 6), and control samples (n = 12) were detected for the expression level of CCDC92 and lipid accumulation. Two types of diabetic mice model (db/dband HFD/STZ) in podocyte-specificCcdc92knockout background were generated to clarify the role of CCDC92 in podocyte lipotoxicity.ResultsThe level of CCDC92 was increased in renal biopsies sections from patients with DKD, which was correlated with eGFR and lipid accumulation in glomeruli. In animal studies, CCDC92 were also induced in the kidney from two independent diabetic models, especially in podocytes. Podocyte-specific deletion ofCcdc92ameliorated podocyte injury and ectopic lipid deposition under diabetic condition. Mechanically, CCDC92 promoted podocyte lipotoxicity, at least in part through ABCA1 signaling-mediated lipid homeostasis.ConclusionOur studies demonstrates that CCDC92 acts as a novel regulator of lipid homeostasis to promote podocyte injury in DKD, suggesting that CCDC92 might be a potential biomarker of podocyte injury in DKD, and targeting CCDC92 may be an effective innovative therapeutic strategy for patients with DKD.