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SMPDL3b modulates insulin receptor signaling in diabetic kidney disease

Author

Listed:
  • A. Mitrofanova

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • S. K. Mallela

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • G. M. Ducasa

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • T. H. Yoo

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine
    Yonsei University)

  • E. Rosenfeld-Gur

    (Weizmann Institute of Science)

  • I. D. Zelnik

    (Weizmann Institute of Science)

  • J. Molina

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • J. Varona Santos

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • M. Ge

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • A. Sloan

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • J. J. Kim

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • C. Pedigo

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine
    Yale University School of Medicine)

  • J. Bryn

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • I. Volosenco

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine
    Lewis Gale Medical Center)

  • C. Faul

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine
    University of Alabama at Birmingham)

  • Y. H. Zeidan

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine
    American University of Beirut)

  • C. Garcia Hernandez

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • A. J. Mendez

    (University of Miami, Miller School of Medicine)

  • I. Leibiger

    (Karolinska Institutet)

  • G. W. Burke

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • A. H. Futerman

    (Weizmann Institute of Science)

  • L. Barisoni

    (University of Miami, Miller School of Medicine)

  • Y. Ishimoto

    (University of Tokyo Graduate School of Medicine
    University of Tokyo Graduate School of Medicine)

  • R. Inagi

    (University of Tokyo Graduate School of Medicine
    University of Tokyo Graduate School of Medicine)

  • S. Merscher

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • A. Fornoni

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

Abstract

Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme that regulates plasma membrane (PM) fluidity. Here we report that SMPDL3b excess, as observed in podocytes in diabetic kidney disease (DKD), impairs insulin receptor isoform B-dependent pro-survival insulin signaling by interfering with insulin receptor isoforms binding to caveolin-1 in the PM. SMPDL3b excess affects the production of active sphingolipids resulting in decreased ceramide-1-phosphate (C1P) content as observed in human podocytes in vitro and in kidney cortexes of diabetic db/db mice in vivo. Podocyte-specific Smpdl3b deficiency in db/db mice is sufficient to restore kidney cortex C1P content and to protect from DKD. Exogenous administration of C1P restores IR signaling in vitro and prevents established DKD progression in vivo. Taken together, we identify SMPDL3b as a modulator of insulin signaling and demonstrate that supplementation with exogenous C1P may represent a lipid therapeutic strategy to treat diabetic complications such as DKD.

Suggested Citation

  • A. Mitrofanova & S. K. Mallela & G. M. Ducasa & T. H. Yoo & E. Rosenfeld-Gur & I. D. Zelnik & J. Molina & J. Varona Santos & M. Ge & A. Sloan & J. J. Kim & C. Pedigo & J. Bryn & I. Volosenco & C. Faul, 2019. "SMPDL3b modulates insulin receptor signaling in diabetic kidney disease," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10584-4
    DOI: 10.1038/s41467-019-10584-4
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