SMPDL3b modulates insulin receptor signaling in diabetic kidney disease

Alla Mitrofanova ,Reiko Inagi ,Shamroop Kumar Mallela ,Armando J Mendez ,Javier Varona Santos ,Eden Rosenfeld-Gur ,C Hernández ,Laura Barisoni ,Christopher E Pedigo ,Alexis Sloan ,George W Burke ,Judith Molina ,Ion Volosenco ,Ingo B Leibiger ,Jonathan Bryn ,Sandra Merscher ,Jin Ju Kim ,Tae‐Hyun Yoo ,G Michelle Ducasa ,Mengyuan Ge ,Iris Daphne Zelnik ,Youssef H Zeidan ,Christian Faul ,Yu Ishimoto ,Anthony H Futerman ,Alessia Fornoni

doi:10.1038/s41467-019-10584-4

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.

Highlights

Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme that regulates plasma membrane (PM) fluidity
Among signaling complexes located in raft domains that are heavily dependent on the PM lipid composition, we are focused on the insulin receptor (IR)signaling complex for several reasons: (1) IR signaling is a key modulator of podocyte function[10,11,12]; (2) SMPDL3b is strongly upregulated in glomeruli of patients with insulin resistance and diabetic kidney disease (DKD)[3]; (3) IR exists in two isoforms which are characterized by distinct affinities for lipid raft domains[13] and which are differentially expressed in various cell types suggesting distinct functions
We previously described SMPDL3b as an enzyme expressed in podocyte lipid rafts that might play an important role in the pathogenesis of proteinuric kidney diseases[2,3]

Summary

Introduction

Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme that regulates plasma membrane (PM) fluidity. 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. We have identified sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) as a lipid raft enzyme that regulates integrin activation, cell migration, and cell survival in podocytes, which are terminally differentiated and specialized cells of the kidney glomerulus[2,3]. Our findings shed some light on the complexity of IR signaling, demonstrate an important role of SMPDL3b in the modulation of insulin signaling, and provide the first evidence that biologically active lipids, such as C1P may represent treatment options for complications of diabetes associated with high cardiovascular morbidity and mortality such as DKD

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