@article{17fa438a8cde4b34ac7cc2cc1614886d,
title = "SMPDL3b modulates insulin receptor signaling in diabetic kidney disease",
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.",
author = "A. Mitrofanova and Mallela, {S. K.} and Ducasa, {G. M.} and Yoo, {T. H.} and E. Rosenfeld-Gur and Zelnik, {I. D.} and J. Molina and Santos, {J. Varona} and M. Ge and A. Sloan and Kim, {J. J.} and C. Pedigo and J. Bryn and I. Volosenco and C. Faul and Zeidan, {Y. H.} and Hernandez, {C. Garcia} and Mendez, {A. J.} and I. Leibiger and Burke, {G. W.} and Futerman, {A. H.} and L. Barisoni and Y. Ishimoto and R. Inagi and S. Merscher and A. Fornoni",
note = "A.F. and S.M. are supported by the NIH grants DK104753, DK11759 and CA227493. A.F. is supported by the NIH grants DK090316, U24DK076169, U54DK083912, UM1DK100846, and 1UL1TR000460. A.F., S.M., C.F. are supported by Hoffman-La Roche. G.M.D. is supported by a Predoctoral Fellowship of the American Heart Association (16PRE30200010). JJK is supported by NRSA Post-doctoral fellowship from NIH/NIDDK (F32DK115109). We thank Dr. Chalfant for his suggestions in the design of exogenous C1P experiments in vivo. We thank Dr. Heinz the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences for a kind gift of HA-tagged human wildtype and mutant SMPDL3b constructs. We would like to acknowledge the skilled assistance of the Flow Cytometry Shared Resource and the Analytical Imaging Shared Resource of the Sylvester Comprehensive Cancer Center at the University of Miami, Miller School of Medicine, for the provision of the sophisticated fluorescence analysis. A.M. performed the in vitro and in vivo experiments, analyzed the data, and wrote methods and results of the manuscript. S.K.M. prepared material for illumina sequencing RNA data analysis, analyzed presence of enriched functional-related gene groups, performed endogenous co-IP experiments, and performed some of the in vivo experiments. G.M.D. performed WT1 histological staining and some in vitro experiments. J.M. performed PSR histological staining and analysis and some in vitro experiments. T.H.Y. initialized the characterization of the podocyte-specific Smpdl3b knockout mice colony. E.R.-G. and I.D.Z. performed C6 ceramide production assay in HEK293 cells and in podocytes using purified SMPDL3b protein. J.V.S., C.G.H., C.P., M.G., A.S., J.J.K. performed some of the in vitro experiments. J.B. and I.V. performed genotyping procedures and some of the in vitro experiments. C.F. designed some of the immunoprecipitation experiments. Y.Z. and A.J.M. designed experiments related to sphingolipid analysis. Y.Z. analyzed some of the mass spec data. I.L. designed and provided human insulin receptor isoforms plasmids. G.W.B. conceived one of the techniques utilized. A.H.F. designed C6 ceramide production experiments. L.B. evaluated kidney tissue slides for histopathology. Y.I. and R.I. performed TEM experiments. S.M. and A.F. conceived the project, designed and supervised the study, analyzed the data, and edited the manuscript. A.F. wrote introduction and discussion of the manuscript, she is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.",
year = "2019",
month = jun,
day = "19",
doi = "https://doi.org/10.1038/s41467-019-10584-4",
language = "الإنجليزيّة",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}