2024年1月16日，《中国药理学报》在线发表了山东大学Fan Yi等研究人员的最新合作成果。该研究显示，CCDC92通过调节PA28α/ABCA1/胆固醇外流轴促进2型糖尿病小鼠足细胞损伤。

研究人员表示，由细胞胆固醇外流障碍介导的足细胞脂肪毒性在糖尿病肾病（DKD）的发病过程中起着至关重要的作用，因此确定调节足细胞胆固醇平衡的潜在治疗靶点具有重要的临床意义。含盘旋线圈结构域92（CCDC92）是一种与代谢紊乱和胰岛素抵抗有关的新型分子。然而，CCDC92在肾实质细胞中的表达水平是否发生变化以及CCDC92在足细胞中的作用仍不清楚。

研究人员发现，Ccdc92在2型糖尿病小鼠的肾小球中被显著诱导，尤其是在足细胞中。重要的是，Ccdc92在肾小球中的上调与尿白蛋白-肌酐比值（UACR）升高和足细胞丢失呈正相关。从功能上讲，足细胞特异性地缺失Ccdc92可减轻DKD小鼠的蛋白尿、肾小球扩张和足细胞损伤。研究人员进一步证实，Ccdc92通过抑制胆固醇外流而导致脂质积累，最终促进了足细胞损伤。

从机理上讲，Ccdc92通过调节PA28α介导的蛋白酶体活性促进ABCA1的降解，进而减少胆固醇外流。因此，这项研究表明，Ccdc92通过调节PA28α/ABCA1/胆固醇外流轴导致了DKD中足细胞的损伤。

附：英文原文

Title: CCDC92 promotes podocyte injury by regulating PA28α/ABCA1/cholesterol efflux axis in type 2 diabetic mice

Author: Zuo, Fu-wen, Liu, Zhi-yong, Wang, Ming-wei, Du, Jun-yao, Ding, Peng-zhong, Zhang, Hao-ran, Tang, Wei, Sun, Yu, Wang, Xiao-jie, Zhang, Yan, Xie, Yu-sheng, Wu, Ji-chao, Liu, Min, Wang, Zi-ying, Yi, Fan

Issue&Volume: 2024-01-16

Abstract: Podocyte lipotoxicity mediated by impaired cellular cholesterol efflux plays a crucial role in the development of diabetic kidney disease (DKD), and the identification of potential therapeutic targets that regulate podocyte cholesterol homeostasis has clinical significance. Coiled-coil domain containing 92 (CCDC92) is a novel molecule related to metabolic disorders and insulin resistance. However, whether the expression level of CCDC92 is changed in kidney parenchymal cells and the role of CCDC92 in podocytes remain unclear. In this study, we found that Ccdc92 was significantly induced in glomeruli from type 2 diabetic mice, especially in podocytes. Importantly, upregulation of Ccdc92 in glomeruli was positively correlated with an increased urine albumin-to-creatinine ratio (UACR) and podocyte loss. Functionally, podocyte-specific deletion of Ccdc92 attenuated proteinuria, glomerular expansion and podocyte injury in mice with DKD. We further demonstrated that Ccdc92 contributed to lipid accumulation by inhibiting cholesterol efflux, finally promoting podocyte injury. Mechanistically, Ccdc92 promoted the degradation of ABCA1 by regulating PA28α-mediated proteasome activity and then reduced cholesterol efflux. Thus, our studies indicate that Ccdc92 contributes to podocyte injury by regulating the PA28α/ABCA1/cholesterol efflux axis in DKD.

DOI: 10.1038/s41401-023-01213-4

Source: https://www.nature.com/articles/s41401-023-01213-4

期刊信息

Acta Pharmacologica Sinica：《中国药理学报》，创刊于1980年。隶属于施普林格·自然出版集团，最新IF：8.2

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