title: β-Arrestins promote podocyte injury by inhibition of autophagy in diabetic nephropathy.
abstract: β-Arrestins are multifunctional proteins originally identified as negative adaptors of G protein-coupled receptors (GPCRs). Emerging evidence has also indicated that β-arrestins can activate signaling pathways independent of GPCR activation. This study was to elucidate the role of β-arrestins in diabetic nephropathy (DN) and hypothesized that β-arrestins contribute to diabetic renal injury by mediating podocyte autophagic process. We first found that both β-arrestin-1 and β-arrestin-2 were upregulated in the kidney from streptozotocin-induced diabetic mice, diabetic db/db mice and kidney biopsies from diabetic patients. We further revealed that either β-arrestin-1 or β-arrestin-2 deficiency (Arrb1(-/-) or Arrb2(-/-)) ameliorated renal injury in diabetic mice. In vitro, we observed that podocytes increased both β-arrestin-1 and β-arrestin-2 expression levels under hyperglycemia condition and further demonstrated that β-arrestin-1 and β-arrestin-2 shared common mechanisms to suppress podocyte autophagy by negative regulation of ATG12-ATG5 conjugation. Collectively, this study for the first time demonstrates that β-arrestin-1 and β-arrestin-2 mediate podocyte autophagic activity, indicating that β-arrestins are critical components of signal transduction pathways that link renal injury to reduce autophagy in DN. Modulation of these pathways may be an innovative therapeutic strategy for treating patients with DN.
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Q X
authors.initials: QX
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: X J
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Duan
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: X
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: J P
authors.identifier: http://orcid.org/0000-0003-3572-1580
authors.initials: JP
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan 250012, China.|Institute of Nephrology, Shandong University, Jinan 250012, China.
authors.forename: F
authors.initials: F
authors.lastname: Yi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D000071183:Autophagy-Related Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050199:Podocytes / Q000166:cytology / Q000378:metabolism; D034622:RNA Interference; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000071557:beta-Arrestins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071183:Autophagy-Related Proteins; D053773:Transforming Growth Factor beta1; D000071557:beta-Arrestins; C025946:3-methyladenine; D044763:Ubiquitin-Conjugating Enzymes; D058546:Class III Phosphatidylinositol 3-Kinases; C568853:Atg3 protein, mouse; D005947:Glucose; D000225:Adenine