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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.
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1 Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA; Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA
2 Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA
3 Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA; Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, FL, USA
4 Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA; Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea
5 Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel
6 Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
7 Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA; Lewis Gale Medical Center, Salem, VI, USA
8 Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA; Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
9 Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA; Department of Radiation Oncology, University of Miami, Miller School of Medicine, Miami, FL, USA; Department of Radiation Oncology, American University of Beirut, Beirut, Lebanon
10 Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA; Department of Radiation Oncology, University of Miami, Miller School of Medicine, Miami, FL, USA
11 Diabetes Research Institute, University of Miami, Miller School of Medicine, Miami, FL, USA
12 The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
13 Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA; Diabetes Research Institute, University of Miami, Miller School of Medicine, Miami, FL, USA
14 Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL, USA
15 Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan; Division of CKD Pathophysiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan