Glucocorticoid-mediated acetylated regulation of glucocorticoid receptor and Histone3/Histone4 influence glucocorticoid heterogeneity in children patients with primary nephrotic syndrome.

Background: Glucocorticoid (GC) response heterogeneity has been recognized as an unfavorable prognostic factor, yet the underlying mechanism remains elusive. In this study, we endeavored to investigate the potential causes from an epigenetic perspective.

Methods: The protein expression levels of the glucocorticoid receptor (GR), acetylated GC receptor (Ac-GR), acetylated histone3 (Ac-H3), histone4 (Ac-H4), and the activity of nuclear factor-κB (NF-κB) were quantified in the peripheral blood lymphocytes of patients exhibiting diverse GC responses.

Results: Before GC treatment, the study included 32 children with steroid-sensitive nephrotic syndrome (SSNS) and 15 children with steroid-resistant nephrotic syndrome (SRNS). The expression levels of Ac-GR, Ac-H3, Ac-H4, and NF-κB activity were significantly different among the control, SSNS, and SRNS groups (p-values < 0.05). Specifically, the expressions were relatively low in the control group, moderately high in the SSNS group, and significantly elevated in the SRNS group. After GC treatment, the expressions of Ac-GR, Ac-H3, Ac-H4, and NF-κB activity decreased in the SSNS children (mean = 0.397, SD = 0.049, p = 4.42E-11 for NF-κB; mean = 0.429, SD = 0.107, p = 8.41E-6 for Ac-GR, mean = 0.652, SD = 0.126, p = 5.38E-8 for Ac-H3, and mean = 0.599, SD = 0.098, p = 1.24E-7 for Ac-H4), while they increased in the SRNS patients (mean = 0.576, SD = 0.064, p = 4.53E-5 for NF-κB, mean = 0.498, SD = 0.113, p = 8.81E-3 for Ac-GR). The correlations among these expressions differed between the SSNS and SRNS groups. In the SSNS group, a positive correlation was identified between NF-κB (mean = -0.156, SD = 0.090) activity and Ac-GR (mean = -0.148, SD = 0.157) protein expression after GC treatment (r = 0.392, p = 0.026), whereas a negative correlation was observed in the SRNS group (mean = 0.195, SD = 0.130 for NF-κB, mean = 0.173, SD = 0.221 for Ac-GR, r = -0.367, p = 0.178). Additionally, a positive correlation for the difference between Ac-H3 and Ac-H4 expressions was observed in the SSNS group (mean = -0.239, SD = 0.190 for Ac-H3, mean = -0.203, SD = 0.168 for Ac-H4, r = 0.394, p = 0.026), which was absent in the SRNS group.

Conclusion: The expression levels of Ac-GR, Ac-H3, and Ac-H4 differed significantly among children's patients with primary nephrotic syndrome (PNS) who manifested distinct GC responses. It is suggested that GC therapy may has a direct impact on the acetylation of GR, H3, and H4.