SMPDL3b modulates insulin receptor signaling in diabetic kidney disease

被引：77

作者：

Mitrofanova, A. ^{[1
,2
,3
]}

Mallela, S. K. ^{[1
,2
]}

Ducasa, G. M. ^{[1
,2
,4
]}

Yoo, T. H. ^{[1
,2
,5
]}

Rosenfeld-Gur, E. ^{[6
]}

Zelnik, I. D. ^{[6
]}

Molina, J. ^{[1
,2
]}

Santos, J. Varona ^{[1
,2
]}

Ge, M. ^{[1
,2
,4
]}

Sloan, A. ^{[1
,2
]}

Kim, J. J. ^{[1
,2
]}

Pedigo, C. ^{[1
,2
,7
]}

Bryn, J. ^{[1
,2
]}

Volosenco, I. ^{[1
,2
,8
]}

Faul, C. ^{[1
,2
,9
]}

Zeidan, Y. H. ^{[2
,10
,11
]}

Hernandez, C. Garcia ^{[1
,2
,10
]}

Mendez, A. J. ^{[12
]}

Leibiger, I. ^{[13
]}

Burke, G. W. ^{[3
,12
]}

Futerman, A. H. ^{[6
]}

Barisoni, L. ^{[14
]}

Ishimoto, Y. ^{[15
,16
]}

Inagi, R. ^{[15
,16
]}

Merscher, S. ^{[1
,2
]}

Fornoni, A. ^{[1
,2
]}

机构：

[1] Univ Miami, Miller Sch Med, Dept Med, Katz Family Div Nephrol & Hypertens, Miami, FL 33136 USA

[2] Univ Miami, Miller Sch Med, Peggy & Harold Katz Family Drug Discovery Ctr, Miami, FL 33136 USA

[3] Univ Miami, Miller Sch Med, Dept Surg, Miami, FL 33136 USA

[4] Univ Miami, Miller Sch Med, Dept Mol & Cellular Pharmacol, Miami, FL 33136 USA

[5] Yonsei Univ, Coll Med, Dept Internal Med, Seoul 03722, South Korea

[6] Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel

[7] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA

[8] Lewis Gale Med Ctr, Salem, VI 24153 USA

[9] Univ Alabama Birmingham, Dept Med, Div Nephrol, Birmingham, AL 35233 USA

[10] Univ Miami, Miller Sch Med, Dept Radiat Oncol, Miami, FL 33136 USA

[11] Amer Univ Beirut, Dept Radiat Oncol, Beirut 11072020, Lebanon

[12] Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA

[13] Karolinska Inst, Rolf Luft Res Ctr Diabet & Endocrinol, S-17176 Stockholm, Sweden

[14] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA

[15] Univ Tokyo, Grad Sch Med, Div Nephrol & Endocrinol, Tokyo 1138654, Japan

[16] Univ Tokyo, Grad Sch Med, Div CKD Pathophysiol, Tokyo 1138654, Japan

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

SPHINGOSINE KINASE 2; CERAMIDE; 1-PHOSPHATE; CELL-MIGRATION; SPHINGOSINE-1-PHOSPHATE; EXPRESSION; RESISTANT; SPHINGOLIPIDS; DEFICIENCY; INHIBITION; CAVEOLIN;

D O I：

10.1038/s41467-019-10584-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：16

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