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Article

Sulfatase 2 Is Associated with Steroid Resistance in Childhood Nephrotic Syndrome

1
Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
2
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
3
Battelle Center for Mathematical Medicine at Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
4
Department of Mathematics, University of Oviedo, 33033 Oviedo, Spain
5
Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
6
Department of Cancer Biology and Genetics, Center for Pharmacogenomics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
*
Authors to whom correspondence should be addressed.
Participating Members of the Pediatric Nephrology Research Consortium are provided in the Appendix A.
Academic Editor: Brad H. Rovin
J. Clin. Med. 2021, 10(3), 523; https://doi.org/10.3390/jcm10030523
Received: 30 December 2020 / Revised: 20 January 2021 / Accepted: 23 January 2021 / Published: 2 February 2021
(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)
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. View Full-Text
Keywords: steroid resistant nephrotic syndrome; sulfatase 2; vascular endothelial growth factor (VEGF); glucocorticoids; FSGS steroid resistant nephrotic syndrome; sulfatase 2; vascular endothelial growth factor (VEGF); glucocorticoids; FSGS
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MDPI and ACS Style

Agrawal, S.; Ransom, R.F.; Saraswathi, S.; Garcia-Gonzalo, E.; Webb, A.; Fernandez-Martinez, J.L.; Popovic, M.; Guess, A.J.; Kloczkowski, A.; Benndorf, R.; Sadee, W.; Smoyer, W.E.; on behalf of the Pediatric Nephrology Research Consortium. Sulfatase 2 Is Associated with Steroid Resistance in Childhood Nephrotic Syndrome. J. Clin. Med. 2021, 10, 523. https://doi.org/10.3390/jcm10030523

AMA Style

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. Sulfatase 2 Is Associated with Steroid Resistance in Childhood Nephrotic Syndrome. Journal of Clinical Medicine. 2021; 10(3):523. https://doi.org/10.3390/jcm10030523

Chicago/Turabian Style

Agrawal, Shipra, Richard F. Ransom, Saras Saraswathi, Esperanza Garcia-Gonzalo, Amy Webb, Juan L. Fernandez-Martinez, Milan Popovic, Adam J. Guess, Andrzej Kloczkowski, Rainer Benndorf, Wolfgang Sadee, William E. Smoyer, and on behalf of the Pediatric Nephrology Research Consortium. 2021. "Sulfatase 2 Is Associated with Steroid Resistance in Childhood Nephrotic Syndrome" Journal of Clinical Medicine 10, no. 3: 523. https://doi.org/10.3390/jcm10030523

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