Sphingomyelinase-Like Phosphodiesterase 3b Expression Levels Determine Podocyte Injury Phenotypes in Glomerular Disease
Sphingomyelinase-Like Phosphodiesterase 3b Expression Levels Determine Podocyte Injury Phenotypes in Glomerular Disease
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DOI：
10.1681/asn.2013111213
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发表时间：
2015-01-01
影响因子：
13.6
通讯作者：
Merscher, Sandra
中科院分区：
文献类型：
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作者：
Yoo, Tae-Hyun;Pedigo, Christopher E.;Merscher, Sandra
在美国，糖尿病肾病 (DKD) 是导致终末期肾病 (ESRD) 的最常见原因。足细胞损伤是 DKD 的一个重要特征，很可能是由葡萄糖以外的循环因素引起的。可溶性尿激酶纤溶酶原激活剂受体 (suPAR) 是一种循环因子，被发现在 FSGS 患者的血清中升高，并在体外引起足细胞 α V beta(3) 整合素依赖性迁移。此外，αVβ(3) 整合素激活与 FSGS 患者肾活检标本中酸性鞘磷脂酶样磷酸二酯酶 3b (SMPDL3b) 足细胞特异性表达减少有关。然而，suPAR依赖性αVβ(3)整合素激活是否发生在FSGS以外的疾病中，以及循环suPAR水平与足细胞中SMPDL3b表达之间是否存在直接联系仍有待确定。我们的数据表明 DKD 患者的血清 suPAR 水平也升高。然而，与 FSGS 不同的是，DKD 患者和经 DKD 血清处理的人足细胞的肾小球中 SMPDL3b 表达增加，通过与 suPAR 相互作用阻止 alpha V beta(3) 整合素激活，并导致 RhoA 活性增加，使足细胞更容易凋亡。在体内，抑制酸性鞘磷脂酶可以减少实验性 DKD 中的蛋白尿，但不能减少 FSGS，这表明 SMPDL3b 表达水平决定了足细胞损伤表型。这些观察结果表明，SMPDL3b 可能是足细胞功能的重要调节剂，可将 suPAR 介导的足细胞损伤从迁移表型转变为凋亡表型，并且它代表了一种新的治疗肾小球疾病的靶点。
Diabetic kidney disease (DKD) is the most common cause of ESRD in the United States. Podocyte injury is an important feature of DKD that is likely to be caused by circulating factors other than glucose. Soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor found to be elevated in the serum of patients with FSGS and causes podocyte alpha V beta(3) integrin-dependent migration in vitro. Furthermore, alpha V beta(3) integrin activation occurs in association with decreased podocyte-specific expression of acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3b) in kidney biopsy specimens from patients with FSGS. However, whether suPAR-dependent alpha V beta(3) integrin activation occurs in diseases other than FSGS and whether there is a direct link between circulating suPAR levels and SMPDL3b expression in podocytes remain to be established. Our data indicate that serum suPAR levels are also elevated in patients with DKD. However, unlike in FSGS, SMPDL3b expression was increased in glomeruli from patients with DKD and DKD sera-treated human podocytes, where it prevented alpha V beta(3) integrin activation by its interaction with suPAR and led to increased RhoA activity, rendering podocytes more susceptible to apoptosis. In vivo, inhibition of acid sphingomyelinase reduced proteinuria in experimental DKD but not FSGS, indicating that SMPDL3b expression levels determined the podocyte injury phenotype. These observations suggest that SMPDL3b may be an important modulator of podocyte function by shifting suPAR-mediated podocyte injury from a migratory phenotype to an apoptotic phenotype and that it represents a novel therapeutic glomerular disease target.