Dataset Information

Reciprocal Relationship Between HDAC2 and P-Glycoprotein/MRP-1 and Their Role in Steroid Resistance in Childhood Nephrotic Syndrome.

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 ?M, and Trichostatin A, 0.8 ?M, 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.

SUBMITTER: Singh H

PROVIDER: S-EPMC6540828 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Reciprocal Relationship Between HDAC2 and P-Glycoprotein/MRP-1 and Their Role in Steroid Resistance in Childhood Nephrotic Syndrome.

Singh Harshit H Agarwal Vikas V Chaturvedi Saurabh S Misra Durga Prasanna DP Jaiswal Akhilesh Kumar AK Prasad Narayan N

Frontiers in pharmacology 20190522

<b>Background:</b> 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. <b>Aim:</b> To evaluate mRNA expression of P-gp/MRP-1 and HDAC2 in PBMCs of steroid sensit ...[more]

PMID: 31191307

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Project description:BACKGROUND:Few data exist for the genetic variants underlying the risk for steroid-sensitive nephrotic syndrome (SSNS) in children. The objectives of this study were to evaluate HLA-DQA1 and APOL1 variants as risk factors for SSNS in African American children and use classic HLA antigen types and amino acid inference to refine the HLA-DQA1 association. STUDY DESIGN:Case-control study. SETTING & PARTICIPANTS:African American children with SSNS or steroid-resistant nephrotic syndrome (SRNS) were enrolled from Duke University and centers participating in the Midwest Pediatric Nephrology Consortium. FACTOR:Genetic variants in HLA-DQA1 (C34Y [rs1129740]; F41S [rs1071630]) and APOL1 high-risk alleles. OUTCOMES:SSNS and SRNS. MEASUREMENTS:Direct sequencing for the HLA-DQA1 and APOL1 variants in 115 African American children (65 with SSNS and 50 with SRNS). Imputation of classic HLA alleles and amino acids was done in 363 South Asian children. RESULTS:The 2 HLA-DQA1 variants were significantly associated with SSNS in African American children (C34Y: P=5.7 × 10-11; OR, 3.53; 95% CI, 2.33-5.42; F41S: P=1.2 × 10-13; OR, 4.08; 95% CI, 2.70-6.28), but not with SRNS (C34Y: P=0.6; F41S: P=0.2). APOL1 high-risk variants were not associated with SSNS (P=0.5) but showed significant associations with SRNS (P=1.04 × 10-7; OR, 4.17; 95% CI, 2.23-7.64). HLA-DQA1*0201, HLA-DQB1*0201, and HLA-DRB1*0701 were the classic HLA alleles with the most significant associations with SSNS risk. The most significantly associated amino acid positions were HLA-DQ?1 56 and 76 (both P=2.8 × 10-7). Conditional analysis revealed that these variants most likely account for the observed association. LIMITATIONS:Modest sample size and limited statistical power to detect small to moderate effect sizes. Children studied may not be representative of all African American children in the United States. CONCLUSIONS:HLA-DQA1 is a risk locus for SSNS, but not SRNS, in African American children, consistent with its role in SSNS risk in children of European, Asian, and African ancestries. There is little evidence of a significant role for the APOL1 high-risk alleles in childhood SSNS in African American children. Refinement of the HLA-DQA1 association identified the critical classic HLA antigen types and amino acids of the HLA-DQ ?1 molecule.

Dataset Information

Reciprocal Relationship Between HDAC2 and P-Glycoprotein/MRP-1 and Their Role in Steroid Resistance in Childhood Nephrotic Syndrome.

Publications

Reciprocal Relationship Between HDAC2 and P-Glycoprotein/MRP-1 and Their Role in Steroid Resistance in Childhood Nephrotic Syndrome.

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