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SMPDL3b modulates insulin receptor signaling in diabetic kidney disease.

Publication ,  Journal Article
Mitrofanova, A; Mallela, SK; Ducasa, GM; Yoo, TH; Rosenfeld-Gur, E; Zelnik, ID; Molina, J; Varona Santos, J; Ge, M; Sloan, A; Kim, JJ; Bryn, J ...
Published in: Nat Commun
June 19, 2019

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.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

June 19, 2019

Volume

10

Issue

1

Start / End Page

2692

Location

England

Related Subject Headings

  • Treatment Outcome
  • Sphingomyelin Phosphodiesterase
  • Signal Transduction
  • Receptor, Insulin
  • Protein Isoforms
  • Podocytes
  • Mice, Knockout
  • Mice
  • Male
  • Insulin
 

Citation

APA
Chicago
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Mitrofanova, A., Mallela, S. K., Ducasa, G. M., Yoo, T. H., Rosenfeld-Gur, E., Zelnik, I. D., … Fornoni, A. (2019). SMPDL3b modulates insulin receptor signaling in diabetic kidney disease. Nat Commun, 10(1), 2692. https://doi.org/10.1038/s41467-019-10584-4
Mitrofanova, A., S. K. Mallela, G. M. Ducasa, T. H. Yoo, E. Rosenfeld-Gur, I. D. Zelnik, J. Molina, et al. “SMPDL3b modulates insulin receptor signaling in diabetic kidney disease.Nat Commun 10, no. 1 (June 19, 2019): 2692. https://doi.org/10.1038/s41467-019-10584-4.
Mitrofanova A, Mallela SK, Ducasa GM, Yoo TH, Rosenfeld-Gur E, Zelnik ID, et al. SMPDL3b modulates insulin receptor signaling in diabetic kidney disease. Nat Commun. 2019 Jun 19;10(1):2692.
Mitrofanova, A., et al. “SMPDL3b modulates insulin receptor signaling in diabetic kidney disease.Nat Commun, vol. 10, no. 1, June 2019, p. 2692. Pubmed, doi:10.1038/s41467-019-10584-4.
Mitrofanova A, Mallela SK, Ducasa GM, Yoo TH, Rosenfeld-Gur E, Zelnik ID, Molina J, Varona Santos J, Ge M, Sloan A, Kim JJ, Pedigo C, Bryn J, Volosenco I, Faul C, Zeidan YH, Garcia Hernandez C, Mendez AJ, Leibiger I, Burke GW, Futerman AH, Barisoni L, Ishimoto Y, Inagi R, Merscher S, Fornoni A. SMPDL3b modulates insulin receptor signaling in diabetic kidney disease. Nat Commun. 2019 Jun 19;10(1):2692.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

June 19, 2019

Volume

10

Issue

1

Start / End Page

2692

Location

England

Related Subject Headings

  • Treatment Outcome
  • Sphingomyelin Phosphodiesterase
  • Signal Transduction
  • Receptor, Insulin
  • Protein Isoforms
  • Podocytes
  • Mice, Knockout
  • Mice
  • Male
  • Insulin