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

Author

Listed:
  • 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
    Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology)

  • 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
    University of Health Sciences, Khayaban-e-Jamia Punjab)

  • 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)

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.

Suggested Citation

  • Thati Madhusudhan & Hongjie Wang & Wei Dong & Sanchita Ghosh & Fabian Bock & Veera Raghavan Thangapandi & Satish Ranjan & Juliane Wolter & Shrey Kohli & Khurrum Shahzad & Florian Heidel & Martin Krueg, 2015. "Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy," Nature Communications, Nature, vol. 6(1), pages 1-15, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7496
    DOI: 10.1038/ncomms7496
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    Cited by:

    1. Ji-Hee Kim & Kyu-Hee Hwang & Bao T. N. Dang & Minseob Eom & In Deok Kong & Yousang Gwack & Seyoung Yu & Heon Yung Gee & Lutz Birnbaumer & Kyu-Sang Park & Seung-Kuy Cha, 2021. "Insulin-activated store-operated Ca2+ entry via Orai1 induces podocyte actin remodeling and causes proteinuria," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Abigail C. Lay & Van Du T. Tran & Viji Nair & Virginie Betin & Jennifer A. Hurcombe & Alexandra F. Barrington & Robert JP Pope & Frédéric Burdet & Florence Mehl & Dmytro Kryvokhyzha & Abrar Ahmad & Ma, 2024. "Profiling of insulin-resistant kidney models and human biopsies reveals common and cell-type-specific mechanisms underpinning Diabetic Kidney Disease," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Yujun Hao & Baoyu He & Liping Wu & Yamu Li & Chao Wang & Ting Wang & Longci Sun & Yanhua Zhang & Yangyang Zhan & Yiqing Zhao & Sanford Markowitz & Martina Veigl & Ronald A. Conlon & Zhenghe Wang, 2022. "Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Moh’d Mohanad Al-Dabet & Khurrum Shahzad & Ahmed Elwakiel & Alba Sulaj & Stefan Kopf & Fabian Bock & Ihsan Gadi & Silke Zimmermann & Rajiv Rana & Shruthi Krishnan & Dheerendra Gupta & Jayakumar Manoha, 2022. "Reversal of the renal hyperglycemic memory in diabetic kidney disease by targeting sustained tubular p21 expression," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Panpan Wang & Victor CY Mak & Ling Rao & Qiuqiu Wu & Yuan Zhou & Rakesh Sharma & S. Chul Kwon & Lydia WT Cheung, 2025. "p85β acts as a transcription cofactor and cooperates with BCLAF1 in the nucleus," Nature Communications, Nature, vol. 16(1), pages 1-20, December.

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