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.
Bibliographical noteFunding Information:
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.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)