Objective To investigate the protective effect of AKAP12/PCK6 signaling pathway on podocyte autophagy in diabetic kidney disease(DKD).Methods A total of 40 C57/B6 AKAP12 KO(AKAP12-/-)mice and wild-type(WT)littermates were randomly divided into four groups,with 10 mice in each group:Ctrl+WT group,Ctrl+AKAP12-/-group,DKD+WT group and DKD+AKAP12-/-group.Primary podocytes were obtained from AKAP12-/-mice and WT mice,and exposed to high glucose(HG,30 mmol/L)or mannitol for 24 h to investigate the mitosis and autophagy of podocytes.The primary podocytes were divided into Mannitol+WT,G+WT,Mannitol+AKAP12-/-and HG+AKAP12-/-.In addition,AKAP12-/-podocytes were transfected with sh-PCSK6 to knockdown the expression of PCK6.Mito-Tracker staining was used to analyze the morphology of mitochondria in podocytes.The expressions of mitotic proteins(FIS1 and DRP1),mitochondrial autophagy(PINK1 and Parkin)and autophagy-related proteins(LC3 and p62)were analyzed by Western blot.Results Compared with HG+WT group,the number of single mitochondria and the expression of FIS1,DRP1,PINK1,Parkin,LC3Ⅱ and p62 proteins increased,while the average branch length of mitochondria decreased in HG+AKAP12-/-group(P＜0.05).Compared with HG+sh-NC group,the number of single mitochondria and the expression of FIS1,DRP1,PINK1,Parkin and LC3Ⅱ proteins decreased significantly in HG+sh-PCSK6 group(P＜0.05 or P＜0.01),while the average branch length of mitochondria increased significantly(P＜0.05).Conclusions AKAP12/PCSK6 signaling pathway mediates the regulation of mitochondrion division and mitochondrion autophagy in podocytes under HG environment.