Sulfatase 2 Is Associated with Steroid Resistance in Childhood Nephrotic Syndrome.

Shipra Agrawal,William Smoyer,Saras Saraswathi,Andrzej Kloczkowski,Esperanza Garcia-Gonzalo,Rainer Benndorf,Wolfgang Sadee,Amy Webb,Adam Guess,Richard Ransom,Juan Fernandez-Martinez,Milan Popovic

doi:10.3390/jcm10030523

Shipra Agrawal, William Smoyer + Show 10 more

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https://doi.org/10.3390/jcm10030523

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Abstract

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.

Highlights

This article is an open access articleNephrotic syndrome (NS) is among the most common kidney diseases seen in both children and adults [1]
Forty-six patients were clinically phenotyped as sensitive nephrotic syndrome (SSNS), since they achieved complete remission of proteinuria within an average of ~7 weeks of steroid therapy, while 20 patients did not achieve remission and were phenotyped as steroid resistant NS (SRNS)
Since these were newly diagnosed cases of nephrotic syndrome (NS), none of these pediatric patients were exposed to additional steroid sparing immunosuppressive therapies between the collection of the Pre- and Post-therapy sample Twelve patients were subjected to transcriptomic analyses as a discovery cohort and up to a total of 66 patients were used as a validation cohort for subsequent analyses (Table 1)

Summary

Introduction

This article is an open access articleNephrotic syndrome (NS) is among the most common kidney diseases seen in both children and adults [1]. The primary therapy for NS, oral glucocorticoids (GC), fails to induce a remission in ~10–20% of children, which either present with or develop GC resistance later in their course [2,3]. The presence of circulating factors in the plasma of NS patients that mediate disease has been speculated for several decades. The majority of NS patients present with no known underlying etiology and the molecular basis for clinical resistance to GC therapy remains largely unclear [1,7].

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