title: Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy.
abstract: Endoplasmic reticulum (ER) stress is associated with diabetic nephropathy (DN), but its pathophysiological relevance and the mechanisms that compromise adaptive ER signalling in podocytes remain unknown. Here we show that nuclear translocation of the transcription factor spliced X-box binding protein-1 (sXBP1) is selectively impaired in DN, inducing activating transcription factor-6 (ATF6) and C/EBP homology protein (CHOP). Podocyte-specific genetic ablation of XBP1 or inducible expression of ATF6 in mice aggravates DN. sXBP1 lies downstream of insulin signalling and attenuating podocyte insulin signalling by genetic ablation of the insulin receptor or the regulatory subunits phosphatidylinositol 3-kinase (PI3K) p85α or p85β impairs sXBP1 nuclear translocation and exacerbates DN. Corroborating our findings from murine DN, the interaction of sXBP1 with p85α and p85β is markedly impaired in the glomerular compartment of human DN. Thus, signalling via the insulin receptor, p85, and XBP1 maintains podocyte homeostasis, while disruption of this pathway impairs podocyte function in DN.
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany.
authors.forename: Thati
authors.initials: T
authors.lastname: Madhusudhan
authors.affiliation: 1] Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany [2] Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Dong
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany.
authors.forename: Sanchita
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Bock
authors.affiliation: Department of Internal Medicine, Hematology and Oncology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany.
authors.forename: Veera Raghavan
authors.initials: VR
authors.lastname: Thangapandi
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany.
authors.forename: Satish
authors.initials: S
authors.lastname: Ranjan
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Wolter
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany.
authors.forename: Shrey
authors.initials: S
authors.lastname: Kohli
authors.affiliation: 1] Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany [2] University of Health Sciences, Khayaban-e-Jamia Punjab, Lahore 54600, Pakistan.
authors.forename: Khurrum
authors.initials: K
authors.lastname: Shahzad
authors.affiliation: Department of Internal Medicine, Hematology and Oncology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Heidel
authors.affiliation: Institute of Anatomy, University Leipzig, Liebigstrasse 13, 04103 Leipzig, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Krueger
authors.affiliation: Internal Medicine I and Division of Nephrology, University of Heidelberg, Heidelberg 69120, Germany.
authors.forename: Vedat
authors.initials: V
authors.lastname: Schwenger
authors.affiliation: Division of Nephrology and Immunology, University Hospital of the RWTH Aachen University of Technology, Aachen 52074, Germany.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Moeller
authors.affiliation: Institute of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kalinski
authors.affiliation: Division of Medicine, Rush University, Chicago, Illinois 60612, USA.
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.affiliation: Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden 01307, Germany.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany.
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
mesh_terms: D051702:Activating Transcription Factor 6 / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000172:deficiency / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D016208:Databases, Factual; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011972:Receptor, Insulin / Q000172:deficiency / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D013311:Streptozocin; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D000071717:X-Box Binding Protein 1
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D007328:Insulin; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D051742:Transcription Factor CHOP; D013311:Streptozocin; D058543:Class Ia Phosphatidylinositol 3-Kinase; D011972:Receptor, Insulin