SMPDL3b modulates insulin receptor signaling in diabetic kidney disease
SMPDL3b modulates insulin receptor signaling in diabetic kidney disease
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DOI：
10.1038/s41467-019-10584-4
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发表时间：
2019-06-19
影响因子：
16.6
通讯作者：
Fornoni, A.
中科院分区：
文献类型：
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作者：
Mitrofanova, A.;Mallela, S. K.;Fornoni, A.
鞘磷脂磷酸二酯酶酸性样3b（SMPDL 3b）是一种调节质膜（PM）流动性的脂筏酶。在这里，我们报告SMPDL 3b过量，如糖尿病肾病（DKD）足细胞中观察到的，通过干扰胰岛素受体亚型与PM中的小窝蛋白-1结合来损害胰岛素受体亚型B依赖性促生存胰岛素信号传导。SMPDL 3b过量影响活性鞘脂的产生，导致神经酰胺-1-磷酸（C1 P）含量降低，如在体外人足细胞和体内糖尿病db/db小鼠肾皮质中观察到的。db/ db小鼠中足细胞特异性Smpdl 3b缺陷足以恢复肾皮质C1 P含量并保护免于DKD。外源性给予C1 P在体外恢复IR信号传导，并在体内阻止已建立的DKD进展。总之，我们确定SMPDL 3b作为胰岛素信号传导的调节剂，并证明补充外源性C1 P可能代表治疗糖尿病并发症如DKD的脂质治疗策略。
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.