SMPDL3b modulates insulin receptor signaling in diabetic kidney disease.
Authors 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
Submitted By Submitted Externally on 8/2/2019
Status Published
Journal Nature communications
Year 2019
Date Published 6/1/2019
Volume : Pages 10 : 2692
PubMed Reference 31217420
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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