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AKAP1 Mediates High Glucose-Induced Mitochondrial Fission Through the Phosphorylation of Drp1 in Podocytes
45 Pages Posted: 12 Jun 2019
More...Abstract
Increasing evidence suggests that mitochondrial dysfunction plays a critical role in the development of diabetic kidney disease. However, the specific pathomechanism by which hyperglycaemia leads to mitochondrial dysfunction remains unclear. A-kinase anchoring protein (AKAP)1 is a scaffold protein in the AKAP family that is involved in mitochondrial fission and fusion. Here, we show that rats with streptozotocin (STZ)-induced diabetes developed proteinuria and podocyte damage accompanied by AKAP1 overexpression and that AKAP1 closely interacted with the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). At the molecular level, high glucose (HG) induced podocyte injury and Drp1 phosphorylation at Ser637 as evidenced by a reduced mitochondrial potential, increased ROS generation, reduced ATP synthesis, and increased podocyte apoptosis. Furthermore, the AKAP1 knockdown provided protection against HG-induced podocyte injury and suppressed HG-induced Drp1 phosphorylation at Ser637. AKAP1 overexpression aggravated HG-induced mitochondrial fragmentation and podocyte apoptosis. The co-immunoprecipitation assay showed that HG-induced Drp1 interacted with AKAP1, revealing that AKAP1 could interact with Drp1 in response to HG stimulation in podocytes. These findings suggest that AKAP1 is able to recruit Drp1 and contributes to mitochondrial fission in podocytes. Subsequently, we tested the effect of Drp1 phosphorylation at Ser637 on the subcellular localization by transfecting podocytes with Flag-Drp1 (wildtype, WT), HA-Drp1 S637A or HA-Drp1 S637D. We demonstrated that activated AKAP1 promoted Drp1 phosphorylation at Ser637, which promoted the translocation of Drp1 from the cytoplasm to the surface of the mitochondria. These findings indicate that AKAP1 is the primary pathogenic factor in the development and progression of HG-induced podocyte injury via mitochondrial fission by modulating Drp1 phosphorylation in human podocytes.
Funding: This work was supported by grants from the National Science Foundation of China (81770687 and 81570617 to G.D., and 81800615 to Y.M.).
Declaration of Interest: No competing financial interests exist.
Ethical Approval: The animal protocols used in the present study were approved by the animal ethics committee of Wuhan University, Wuhan, China.
Keywords: diabetic kidney disease; podocyte; mitochondrial fission; AKAP1; Drp1
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