Sulfatase 2 Is Associated with Steroid Resistance in Childhood Nephrotic Syndrome.
Sulfatase 2 Is Associated with Steroid Resistance in Childhood Nephrotic Syndrome.
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DOI：
10.3390/jcm10030523
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发表时间：
2021-02-02
影响因子：
3.9
通讯作者：
On Behalf Of The Pediatric Nephrology Research Consortium Pnrc
中科院分区：
文献类型：
--
作者：
Agrawal S;Ransom RF;Saraswathi S;Garcia-Gonzalo E;Webb A;Fernandez-Martinez JL;Popovic M;Guess AJ;Kloczkowski A;Benndorf R;Sadee W;Smoyer WE;On Behalf Of The Pediatric Nephrology Research Consortium Pnrc
糖皮质激素(GC)耐药使约10-20%的肾病综合征(NS)儿童的治疗复杂化，但耐药的分子基础仍不清楚。我们使用RNAseq分析和基于计算机算法的方法对12名儿童在首次出现NS时和经过~7周的GC治疗后的外周血白细胞进行分析，以确定能够区分类固醇抵抗型NS(SRNS)和类固醇敏感型NS(SSNS)的12基因小组。在这个小组中，随后对多达66名儿童的一种生物相关候选硫酸酯酶2(SULF2)的验证和分析显示，SSNS与SRNS相比，治疗后/治疗前SULF2白细胞表达和血浆芳基硫酸酯酶活性的比率都更高。然而，血浆SULF2内切酶活性(通过血管内皮生长因子结合活性测量)和血浆血管内皮生长因子水平都不能区分SSNS和SRNS，尽管有报道称血管内皮生长因子是SULF2在肾小球中的S效应的下游中介。对NS相关的大鼠肾小球和培养足细胞损伤的实验研究也显示，SULF2的表达降低，而GC处理足细胞可部分逆转这一现象。这些发现提示，SULF2的水平和活性与NS的GC耐药有关，SULF2可能通过调节不同于血管内皮生长因子的下游介质在NS中发挥保护作用。
Glucocorticoid (GC) resistance complicates the treatment of ~10–20% of children with nephrotic syndrome (NS), yet the molecular basis for resistance remains unclear. We used RNAseq analysis and in silico algorithm-based approaches on peripheral blood leukocytes from 12 children both at initial NS presentation and after ~7 weeks of GC therapy to identify a 12-gene panel able to differentiate steroid resistant NS (SRNS) from steroid-sensitive NS (SSNS). Among this panel, subsequent validation and analyses of one biologically relevant candidate, sulfatase 2 (SULF2), in up to a total of 66 children, revealed that both SULF2 leukocyte expression and plasma arylsulfatase activity Post/Pre therapy ratios were greater in SSNS vs. SRNS. However, neither plasma SULF2 endosulfatase activity (measured by VEGF binding activity) nor plasma VEGF levels, distinguished SSNS from SRNS, despite VEGF’s reported role as a downstream mediator of SULF2’s effects in glomeruli. Experimental studies of NS-related injury in both rat glomeruli and cultured podocytes also revealed decreased SULF2 expression, which were partially reversible by GC treatment of podocytes. These findings together suggest that SULF2 levels and activity are associated with GC resistance in NS, and that SULF2 may play a protective role in NS via the modulation of downstream mediators distinct from VEGF.
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影响因子：
56.9
作者：
Golub, TR;Slonim, DK;Lander, ES
通讯作者：
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通讯作者：
Quaggin, Susan E.
影响因子：
4.8
作者：
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