Abstract
Background: Reduced HDACs levels have been reported in steroid resistant chronic obstructive pulmonary disease and bronchial asthma patients. P-glycoprotein (P-gp) over expression in peripheral blood mononuclear cells (PBMCs) has been reported in patients with steroid resistant nephrotic syndrome (NS). Whether and how HDACs and P-gp are linked with each other is not clear, especially in NS patients.Aim: To evaluate mRNA expression of P-gp/MRP-1 and HDAC2 in PBMCs of steroid sensitive (SSNS) and steroid resistant nephrotic syndrome (SRNS) patients, and determine the relationship between expression of HDAC2 and P-gp/ MRP-1in NS patients.Methods: Twenty subjects (10 in each group), SSNS (mean age 7.54 ± 3.5 years), and SRNS (mean age 8.43 ± 3.8 years) were recruited. mRNA expression of HDAC2 and P-gp/MRP-1 was studied by quantitative real time PCR. PBMCs were treated with Theophylline, 1 μM, and Trichostatin A, 0.8 μM, for 48 h for induction and suppression of HDAC2, respectively.Results: At baseline, expression of P-gp (4.79 ± 0.10 vs. 2.13 ± 0.12, p < 0.0001) and MRP-1 (3.99 ± 0.08 vs. 1.99 ±0.11, p < 0.0001) on PBMCs were increased whereas, HDAC2 mRNA levels (2.97 ± 0.15 vs. 6.02 ± 0.13, p < 0.0001) were significantly decreased in SRNS as compared to that of SSNS patients. Compared to baseline, theophylline reduced mRNA expression of P-gp and MRP-1 (fold change 2.65 and 2.21, *p < 0.0001 in SRNS) (fold change 1.25, 1.24, *p < 0.0001 in SSNS), respectively. However, it increased the expression of HDAC2 (fold change 5.67, *p < 0.0001 in SRNS) (fold change 6.93, *p < 0.0001 in SSNS). Compared to baseline, TSA treatment increased mRNA levels of P-gp and MRP-1 (fold change 7.51, 7.31, *p < 0.0001 in SRNS) and (fold change 3.49, 3.35, *p < 0.0001 in SSNS), respectively. It significantly decreased the level of HDAC2 (fold change 1.50, *p < 0.0001 in SRNS) (fold change 2.53, *p < 0.0001 in SSNS) patients.Conclusion: Reduced HDAC2 and increased P-gp/MRP-1 activity may play a role in response to steroids in childhood NS. HDAC2 and P-gp/MRP-1 are in reciprocal relationship with each other.
Highlights
Minimal change disease (MCD) is the most common of all the glomerular diseases in children causing Idiopathic Nephrotic Syndrome (INS)
We observed that mRNA levels of histone deacetylase 2 (HDAC2) were reduced while, P-gp/MRP-1 levels were increased in peripheral blood mononuclear cells (PBMCs) of steroid-resistant nephrotic syndrome (SRNS) patients (Figures 1A–C)
MRNA expression of P-gp/MRP1 in three sensitive nephrotic syndrome (SSNS) patients was significantly increased whereas that of HDAC2 was significantly decreased at the time of relapse (Supplementary Figures 1A–C)
Summary
Minimal change disease (MCD) is the most common of all the glomerular diseases in children causing Idiopathic Nephrotic Syndrome (INS). INS is broadly categorized into two groups, steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) (Noone et al, 2018). Almost half of SSNS patients experience relapses of proteinuria within the first 6 months of stopping steroids. Some of these patients may become steroid resistant later on (Hogg et al, 2000). The treatment of relapsing and SRNS patients is challenging and requires immunosuppressive and potentially toxic drugs (Eddy and Symons, 2003). Reduced HDACs levels have been reported in steroid resistant chronic obstructive pulmonary disease and bronchial asthma patients. P-glycoprotein (P-gp) over expression in peripheral blood mononuclear cells (PBMCs) has been reported in patients with steroid resistant nephrotic syndrome (NS). Whether and how HDACs and P-gp are linked with each other is not clear, especially in NS patients
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