title: (Pro)renin receptor regulates autophagy and apoptosis in podocytes exposed to high glucose.
abstract: High glucose reduces autophagy and enhances apoptosis of podocytes. Previously, we reported that high glucose induced podocyte injury through upregulation of the (pro)renin receptor (PRR). We hypothesized that increasing PRR reduces autophagy and increases apoptosis of mouse podocytes exposed to high glucose via activation of the PI3K/Akt/mTOR signaling pathway. Mouse podocytes were cultured in normal (5 mmol/l) or high (25 mmol/l) d-glucose for 48 h. High glucose significantly increased mRNA and protein levels of PRR, phosphorylation of PI3K/Akt/mTOR, and p62. In contrast, high glucose decreased activation of UNC-51-like kinase-1 (ULK1) by phosphorylating Ser⁷⁵⁷ and protein levels of microtubule-associated protein-1 light chain 3B (LC3B)-II and Lamp-2. Bafilomycin A1 increased LC3BII and p62 accumulation in high-glucose-treated cells. High glucose reduced the autophagic flux. Confocal microscopy studies showed significant reduction in the protein level of LC3B in response to high glucose. Cyto-ID autophagy staining showed a significant decrease in autophagosome formation with high glucose. In the absence of PRR, activation of Akt with sc-79 or mTOR with MHY-1485 increased p62 accumulation. Caspase-3/7 activity and apoptosis monitored by TUNEL assay were significantly increased in podocytes treated with high glucose. PRR siRNA significantly reversed the effects of high glucose. Based on these data, we conclude that high glucose decreases autophagy and increases apoptosis in mouse podocytes through the PRR/PI3K/Akt/mTOR signaling pathway.
authors.affiliation: Division of Endocrinology and Metabolism, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Caixia
authors.initials: C
authors.lastname: Li
authors.affiliation: Division of Endocrinology and Metabolism, University of Virginia Health System, Charlottesville, Virginia hms7a@virginia.edu.
authors.forename: Helmy M
authors.initials: HM
authors.lastname: Siragy
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D002460:Cell Line; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism*; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009994:Osmolar Concentration; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D050199:Podocytes / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000093342:Prorenin Receptor
chemical_list: D000071189:Autophagy-Related Protein-1 Homolog; D005947:Glucose; D052119:Lysosomal-Associated Membrane Protein 2; D008869:Microtubule-Associated Proteins; D058539:Phosphatidylinositol 3-Kinase; D017346:Protein Serine-Threonine Kinases; D016271:Proto-Oncogene Proteins c-myc; D006180:Proton-Translocating ATPases; D011956:Receptors, Cell Surface; D058570:TOR Serine-Threonine Kinases; C583530:ATP6AP2 protein, mouse; D000093342:Prorenin Receptor; C480860:Map1lc3b protein, mouse; C489428:Myc protein, mouse; C546843:mTOR protein, mouse; C112444:Ulk1 protein, mouse
keywords: (pro)renin receptor; apoptosis; autophagy; high glucose; podocyte