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

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

机构地区：[1]Department of Pharmacology,School of Basic Medical Sciences,Shandong University,Jinan,250012,China [2]Department of Pathogenic Biology,School of Basic Medical Sciences,Shandong University,Jinan,250012,China [3]National Key Laboratory for Innovation and Transformation of Luobing Theory,Key Laboratory of Cardiovascular Remodeling and Function Research,Chinese Ministry of Education and Chinese Ministry of Health,Qilu Hospital,Shandong University,Jinan,250012,China

出　　处：《Acta Pharmacologica Sinica》2024年第5期1019-1031,共13页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(T2321004,91949202,82090024,81873614,82090021,81900621,81970580,82070753,82170734,81800645,81800643,22107058);Shandong Provincial Natural Science Foundation,China(ZR2019ZD40,ZR2019MH041,2023HWYQ-020);The Taishan Scholars Program of Shandong Province,China(tsqn202306074);Cutting Edge Development Fund of Advanced Medical Research Institute(GYY2023QY01).

摘　　要：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.

关 键 词：CCDC92 proteasome activity PODOCYTES cholesterol efflux diabetic kidney disease 

分 类 号：R587.2[医药卫生—内分泌]