SMPDL3b modulates insulin receptor signaling in diabetic kidney disease

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, Y. H. Zeidan, C. Garcia Hernandez, A. J. Mendez, I. Leibiger, G. W. BurkeA. H. Futerman, L. Barisoni, Y. Ishimoto, R. Inagi, S. Merscher, A. Fornoni

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number2692
JournalNature communications
Volume10
Issue number1
DOIs
Publication statusPublished - 2019 Dec 1

Fingerprint

kidney diseases
Sphingomyelin Phosphodiesterase
insulin
Insulin Receptor
Diabetic Nephropathies
Podocytes
phosphates
Kidney Cortex
acids
Acids
cortexes
kidneys
Cell membranes
mice
lipids
Protein Isoforms
Cell Membrane
Insulin
membranes
Lipids

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

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. Nature communications, 10(1), [2692]. https://doi.org/10.1038/s41467-019-10584-4
Mitrofanova, A. ; Mallela, S. K. ; Ducasa, G. M. ; Yoo, T. H. ; Rosenfeld-Gur, E. ; Zelnik, I. D. ; Molina, J. ; Varona Santos, J. ; Ge, M. ; Sloan, A. ; Kim, J. J. ; Pedigo, C. ; Bryn, J. ; Volosenco, I. ; Faul, C. ; Zeidan, Y. H. ; Garcia Hernandez, C. ; Mendez, A. J. ; Leibiger, I. ; Burke, G. W. ; Futerman, A. H. ; Barisoni, L. ; Ishimoto, Y. ; Inagi, R. ; Merscher, S. ; Fornoni, A. / SMPDL3b modulates insulin receptor signaling in diabetic kidney disease. In: Nature communications. 2019 ; Vol. 10, No. 1.
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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 2019, 'SMPDL3b modulates insulin receptor signaling in diabetic kidney disease', Nature communications, vol. 10, no. 1, 2692. https://doi.org/10.1038/s41467-019-10584-4

SMPDL3b modulates insulin receptor signaling in diabetic kidney disease. / Mitrofanova, A.; Mallela, S. K.; Ducasa, G. M.; Yoo, T. H.; Rosenfeld-Gur, E.; Zelnik, I. D.; Molina, J.; Varona Santos, J.; Ge, M.; Sloan, A.; Kim, J. J.; Pedigo, C.; Bryn, J.; Volosenco, I.; Faul, C.; Zeidan, Y. H.; Garcia Hernandez, C.; Mendez, A. J.; Leibiger, I.; Burke, G. W.; Futerman, A. H.; Barisoni, L.; Ishimoto, Y.; Inagi, R.; Merscher, S.; Fornoni, A.

In: Nature communications, Vol. 10, No. 1, 2692, 01.12.2019.

Research output: Contribution to journalArticle

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AU - Mitrofanova, A.

AU - Mallela, S. K.

AU - Ducasa, G. M.

AU - Yoo, T. H.

AU - Rosenfeld-Gur, E.

AU - Zelnik, I. D.

AU - Molina, J.

AU - Varona Santos, J.

AU - Ge, M.

AU - Sloan, A.

AU - Kim, J. J.

AU - Pedigo, C.

AU - Bryn, J.

AU - Volosenco, I.

AU - Faul, C.

AU - Zeidan, Y. H.

AU - Garcia Hernandez, C.

AU - Mendez, A. J.

AU - Leibiger, I.

AU - Burke, G. W.

AU - Futerman, A. H.

AU - Barisoni, L.

AU - Ishimoto, Y.

AU - Inagi, R.

AU - Merscher, S.

AU - Fornoni, A.

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N2 - 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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Mitrofanova A, Mallela SK, Ducasa GM, Yoo TH, Rosenfeld-Gur E, Zelnik ID et al. SMPDL3b modulates insulin receptor signaling in diabetic kidney disease. Nature communications. 2019 Dec 1;10(1). 2692. https://doi.org/10.1038/s41467-019-10584-4