Histone Deacetylase-2 and Steroid Responsiveness in Pediatric Nephrotic Syndrome: An Epigenetic Perspective from Egyptian Cohorts

Abstract

Background: Nephrotic syndrome (NS) is one of the most common chronic glomerular disorders in childhood, characterized by heavy proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Glucocorticoids remain the cornerstone of therapy, and the initial response to steroid treatment serves as the strongest predictor of long-term outcome. While most children achieve remission with corticosteroids, a substantial proportion develop steroid resistant nephrotic syndrome (SRNS), which is associated with progression to chronic kidney disease and increased morbidity. The mechanisms underlying variable steroid responsiveness remain incompletely understood. Recent research highlights the role of epigenetic regulation, particularly histone modifications, in modulating glucocorticoid receptor (GR) signaling. Histone deacetylase-2 (HDAC2), a class I histone deacetylase, has emerged as a pivotal regulator of glucocorticoid-mediated anti-inflammatory activity by remodeling chromatin and facilitating transcriptional repression of pro-inflammatory genes. Reduced expression or activity of HDAC2 has been implicated in impaired steroid responsiveness in several chronic inflammatory conditions, raising interest in its role in pediatric nephrotic syndrome. This review aims to critically evaluate the relationship between HDAC2 expression and activity and steroid responsiveness in children with nephrotic syndrome, with particular emphasis on Egyptian pediatric cohorts where SRNS prevalence is relatively high. We explore current evidence from preclinical studies, clinical investigations, and genetic/epigenetic research, highlighting how HDAC2 deficiency may contribute to steroid resistance. Furthermore, we discuss the potential utility of HDAC2 as a predictive biomarker and as a therapeutic target for novel epigenetic interventions.

Conclusion: Emerging data suggest that reduced HDAC2 expression and activity contribute to impaired glucocorticoid signaling and poor therapeutic outcomes in pediatric nephrotic syndrome. Egyptian studies provide unique insights into the genetic and environmental determinants influencing HDAC2 function, underscoring population-specific variability in steroid response. Restoration of HDAC2 activity through pharmacological agents, antioxidants, or epigenetic modulators represents a promising therapeutic avenue to enhance steroid sensitivity. However, current evidence remains preliminary, and large-scale, multicenter studies are needed to validate HDAC2 as a reliable biomarker and to evaluate targeted interventions in diverse pediatric populations. Integrating HDAC2 profiling into clinical practice could advance personalized medicine in childhood nephrotic syndrome, improving treatment outcomes and reducing the burden of steroid resistance.