Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy

Thati Madhusudhan (), Hongjie Wang, Wei Dong, Sanchita Ghosh, Fabian Bock, Veera Raghavan Thangapandi, Satish Ranjan, Juliane Wolter, Shrey Kohli, Khurrum Shahzad, Florian Heidel, Martin Krueger, Vedat Schwenger, Marcus J. Moeller, Thomas Kalinski, Jochen Reiser, Triantafyllos Chavakis and Berend Isermann ()
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Thati Madhusudhan: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg
Hongjie Wang: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg
Wei Dong: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg
Sanchita Ghosh: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg
Fabian Bock: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg
Veera Raghavan Thangapandi: Hematology and Oncology, Medical Faculty, Otto-von-Guericke University Magdeburg
Satish Ranjan: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg
Juliane Wolter: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg
Shrey Kohli: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg
Khurrum Shahzad: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg
Florian Heidel: Hematology and Oncology, Medical Faculty, Otto-von-Guericke University Magdeburg
Martin Krueger: Institute of Anatomy, University Leipzig
Vedat Schwenger: University of Heidelberg
Marcus J. Moeller: University Hospital of the RWTH Aachen University of Technology
Thomas Kalinski: Institute of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg
Jochen Reiser: Rush University
Triantafyllos Chavakis: Technische Universität Dresden
Berend Isermann: Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7496

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