title: Apelin promotes diabetic nephropathy by inducing podocyte dysfunction via inhibiting proteasome activities.
abstract: Podocyte injuries are associated with progression of diabetic nephropathy (DN). Apelin, an adipocyte-derived peptide, has been reported to be a promoting factor for DN. In this study, we aim to determine whether apelin promotes progression of DN by inducing podocyte dysfunction. kk-Ay mice were used as models for DN. Apelin and its antagonist, F13A were intraperitoneally administered for 4 weeks, respectively. Renal function and foot process proteins were analysed to evaluate the effects of apelin on kk-Ay mice and podocytes. Apelin increased albuminuria and decreased podocyte foot process proteins expression in kk-Ay mice, which is consistent with the results that apelin receptor (APLNR) levels increased in glomeruli of patients or mice with DN. In cultured podocytes, high glucose increased APLNR expression and apelin administration was associated with increased permeability and decreased foot process proteins levels. All these dysfunctions were associated with decreased 26S proteasome activities and increased polyubiquitinated proteins in both kk-Ay mice and cultured podocytes, as demonstrated by 26S proteasome activation with cyclic adenosine monophosphate (cAMP) or oleuropein. These effects seemed to be related to endoplasmic reticulum (ER) stress, as apelin increased C/EBP homologous protein (CHOP) and peiFα levels while cAMP or oleuropein reduced it in high glucose and apelin treated podocytes. These results suggest that apelin induces podocyte dysfunction in DN through ER stress which was induced by decreased proteasome activities in podocytes.
authors.affiliation: Department of Pathophysiology and Pathology, Capital Medical University, Beijing, China.|Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Caixia
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Pathophysiology and Pathology, Capital Medical University, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology and Pathology, Capital Medical University, Beijing, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Pathophysiology and Pathology, Capital Medical University, Beijing, China.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Pathophysiology and Pathology, Capital Medical University, Beijing, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Wenying
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology and Pathology, Capital Medical University, Beijing, China.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Zeng
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D000075244:Apelin Receptors; D001485:Basement Membrane / Q000187:drug effects / Q000473:pathology; D002463:Cell Membrane Permeability / Q000187:drug effects; D003404:Creatinine / Q000378:metabolism; D000242:Cyclic AMP / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000473:pathology* / Q000503:physiopathology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000009:adverse effects*; D057888:Iridoid Glucosides; D039823:Iridoids / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D050199:Podocytes / Q000187:drug effects / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: D000418:Albumins; D000075244:Apelin Receptors; C491285:Aplnr protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D057888:Iridoid Glucosides; D039823:Iridoids; D061988:Proteasome Inhibitors; D043562:Receptors, G-Protein-Coupled; C532492:apelin-13, Ala(13)-; C002769:oleuropein; D003404:Creatinine; D000242:Cyclic AMP; D046988:Proteasome Endopeptidase Complex; D005947:Glucose
keywords: APLNR; ER stress; apelin; diabetic nephropathy; podocyte; proteasome