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ORIGINAL ARTICLE
Ahead of print publication  

P-glycoprotein and/or Histone Deacetylase 2 Regulates Steroid Responsiveness in Childhood Nephrotic Syndrome


1 Department of Clinical Immunology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Correspondence Address:
Vikas Agarwal,
Department of Clinical Immunology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow - 226 014, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_126_19

  Abstract 


Background: P-glycoprotein (P-gp) overexpression in peripheral blood mononuclear cells (PBMCs) has been reported in patients with steroid-resistant nephrotic syndrome (SRNS). Glucocorticoids suppress NFκB-associated coactivator activity by deacetylation of histone by enzyme histone deacetylase (HDAC)-2. Interaction between HDAC2 activity and P-gp expression in childhood NS patients is not clear.
Aim: This study aims to evaluate the role of HDAC2 and P-gp expression on PBMCs and steroid responsiveness in patients with childhood NS.
Materials and Methods: Thirty-one patients were recruited at baseline (n = 31) (before initiating steroid therapy); after 6 weeks of steroid therapy, 24 patients achieved remission (steroid-sensitive NS [SSNS] n = 24 mean age, 7.96 ± 3.90), whereas seven patients were resistant to steroids (SRNS, n = 7, mean age 10.00 ± 3.55). mRNA expression of HDAC2 and P-gp and functional analysis of P-gp and enzymatic activity of HDAC2 were analyzed at baseline, and at 6 weeks of steroid treatment and at the time of relapse.
Results: The expression of P-gp mRNA was significantly lower in individuals (n = 24) who achieved remission at 6-week steroid therapy as compared to baseline and those who were resistant (n = 7) to steroids (P < 0.005). Similarly, the expression of HDAC2 mRNA was significantly higher at baseline and at remission following 6-week steroid therapy as compared to their expression in those who were resistant to steroids (P < 0.005). The function of P-gp was significantly lower in NS patients who achieved remission after 6-week steroid therapy compared to baseline (P < 0.005), whereas it was not significant in resistant patients (P = 0.37). The enzymatic activity of HDAC2 was significantly higher in SSNS patients as compared SRNS patients at 6-week steroid therapy (P < 0.005).
Conclusion: The expression and function of P-gp and HDAC2 may affect steroid response in NS patients. Combined therapy of steroids with P-gp inhibitor and/or HDAC2 inducers may have a rationale in management of SRNS patients.

Keywords: Histone deacetylases 2, Nephrotic syndrome, P-glycoprotein, steroid-resistant



How to cite this URL:
Singh H, Prasad N, Misra DP, Jaiswal AK, Agarwal V. P-glycoprotein and/or Histone Deacetylase 2 Regulates Steroid Responsiveness in Childhood Nephrotic Syndrome. Indian J Rheumatol [Epub ahead of print] [cited 2019 Dec 8]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=271909




  Introduction Top


Minimal change disease (MCD), is one of the leading glomerular diseases in children which causes nephrotic syndrome (NS), and is characterized by extreme proteinuria, which is caused by damage to podocytes and foot process effacement that leads to alterations in the selective glomerular permeability barrier. The reported incidence of MCD in children varies between 2 and 7 new cases per 100,000 children, MCD remains considerably more common in Asian male.[1],[2] There are certain genetic mutation which encodes proteins essential for the integrity of the glomerular filtration barrier, mainly NPHS1, NPHS2, WT1, PLCE1, LAMB2, and TRPC6.[3] The effectiveness of different immune-suppressive and the crucial role of steroids in the treatment of nongenetic forms of NS strongly implicate the immune system in the pathogenesis of this disease.[4] Based on their response to initial therapy to oral steroids, NS is broadly divided into two major groups as steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS).[5] Corticosteroids suppress activated T-cell and B-cell and synthesis of pro-inflammatory cytokines and up-regulates the production of anti-inflammatory cytokines.[6],[7] Corticosteroids remain the mainstay therapy for many autoimmune diseases despite the availability of targeted therapies such as biological and various immunosuppressive drugs.

The lack of response to steroids in nongenetic form of NS has been linked to inherent or acquired multidrug resistance MDR-1,[8] and has been reported with diseases such as lupus nephritis,[9] systemic lupus erythematosus (SLE),[9] and rheumatoid arthritis (RA).[10] P-glycoprotein (P-gp), a product of MDR-1 gene, which belongs to ATP-binding cassettes (ABCB1) transporters, an energy-dependent efflux pump which on overexpression, reduces the bioavailability of steroids inside the cells, and may limit its efficacy due to insufficient concentration.[5],[11],[12] P-gp is richly expressed in most of the tissues, in the hematopoietic system and peripheral blood lymphocytes, which are the putative targets of pharmacotherapy in NS.[13],[14]

Histone acetylases (HATs) and histone deacetylases (HDACs) are two classes of enzyme that tightly regulates the transcription of any gene in the nucleus. HATs first acetylate the histones of the chromatin structure and open up the firmly coiled DNA structure allowing access to numerous transcription factors present in the immediate vicinity to bind to their target promoter regions and bring about the transcription of various genes. Once transcription signal is over, HDACs remove the acetyl group from lysine amino acid on histone, allowing the histone to wrap DNA tightly and regulate chromatin structure leading to the modulation of inflammatory gene expression.[15],[16]

Corticosteroid suppresses the pro-inflammatory genes by recruiting HDAC2.[17] The role of HDACs in steroid resistance in bronchial asthma and chronic obstructive pulmonary disease and SLE has been suggested.[18],[19] Similarly, there are studies that observed overexpression of P-gp in many autoimmune diseases patients who did not respond to steroids.[9] The recent study in patients with NS has observed that HDAC2 had an effect on steroid response as reduced HDAC2 promoted steroid non-responsiveness.[20] The present study was undertaken to evaluate the role of HDAC2 and P-gp expression on steroid response in patients with NS.


  Materials And Methods Top


Patient recruitment

Thirty-one patients were recruited at baseline (n = 31, mean age 8.42 ± 3.8 (before initiating steroid therapy); from outpatient and inpatient Clinic of Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India. After 6 weeks of steroid therapy, 24 patients responded to steroids and achieved remission (SSNS n = 24), whereas seven patients did not respond to steroids (SRNS, n = 7). All SRNS patients were proven MCD cases as per renal histology. NS in children was defined as proteinuria of 40 mg/m2/h or, the ratio of 2 for spot urine protein (milligram)/creatinine (milligram) in the first-morning urine sample with hypoalbuminemia (serum albumin 40 mg/m2/h or urine dipstick ++ or more) for 3 consecutive days. In cases of infection-associated relapse, blood sample was not collected if there was any clinical evidence of infection in the patients. In three patients with presumed upper respiratory tract viral infection-associated relapse, blood sample for analysis was collected after 2 weeks of resolution of infection when proteinuria was persisting before initiating steroid. Remission was defined as urine protein/creatinine ratio <200 mg/g (<20 mg/mmol) or <1+ of protein on urine dipstick for 3 consecutive days. Steroid resistance was defined as unresponsiveness of 60 mg/m2 body surface area per day for 4 weeks of prednisolone therapy. Patients enrolled in this study did not have any underlying secondary causes; they were negative for hepatitis B surface antigen seropositivity, anti-hepatitis C virus seropositivity, and human immunodeficiency virus seropositivity and had normal serum complement (C3 and C4) levels. An informed consent was obtained from a parent or guardian of patients when participant age was below 7 years as per institute guidelines. This study was performed in accordance with declaration of Helsinki and approved by the Institute Ethics Committee, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.

Human peripheral blood mononuclear cells isolation

Human peripheral blood mononuclear cells (PBMCs) were isolated as previously described protocol.[21]

Reagents

RNAiso Plus was purchased from Takara Bio Inc., Nojihigashi, Kusatsu, Japan. cDNA Synthesis Kit (cat No-K1632) was purchased from Thermo Fisher Scientific Inc., Bartlesville, OK, USA. LightCycler® 480 SYBR Green I Master was purchased from Roche Diagnostics, Indianapolis, IN, USA.

Real-time quantitative polymerase chain reaction analysis

RNA was extracted from PBMCs using RNAiso Plus (Trizol method), and a total of 1 μg of RNA was processed for cDNA synthesis using cDNA Synthesis Kit (Thermo Fisher Scientific Inc., Bartlesville, OK, USA) as per the manufacturer's protocol. We performed real-time polymerase chain reaction (PCR) reactions for each cDNA sample in triplicate using LightCycler® 480 SYBR Green I Master and gene-specific primer pairs for P-gp, HDAC2, and GAPDH. The PCR cycling was as follows: 50°C for 2 min for 1 cycle, 95°C for 10 min for 1 cycle, 95°C for 15 s, and 60°C for 1 min for 40 cycles in light cycler LC480 (Roche, USA). We expressed semi-quantitative real-time PCR data for each target gene as 2–ΔΔCt relative quantitation versus endogenous GAPDH, with error bars representing the standard error of the mean for triplicate reactions and the data being expressed as fold change.[22]

Statistical analysis

Each experiment was performed in triplicates, and average of all experiments was represented as mean ± standard error of the mean. Differences in the various parameters between groups were evaluated by one-way ANNOVA and Student's t-test. Results were considered statistically significant if the P ≤ 0.05. The experiment was performed in three independent series.

Functional assay of P-glycoprotein

P-gp functional assay was performed by flow cytometry of total mononuclear blood cells using a commercially available kit (EFLUXX-ID® Green multidrug resistance assay kit). In brief, cells were preincubated with warm RPMI 1640 medium (indicator free) after two washing steps to remove remaining serum components, followed by 15-min incubation with Rhodamine 123 or calcein-AM dye. After 90-min incubation in medium with or without verapamil as P-gp inhibitor, fluorescence was measured with a FACS Canto cytometer (Becton Dickinson, Mount View, CA, USA). Multiresistance Activity Factor for each transporter was calculated using the formula (MAR Pgp= (100*F Pgp-F0)/Fpgp).

Enzyme activity of histone deacetylase 2

The activity of HDAC2 in the lymphocytes was measured using the human HDAC2 activity assay kit. HDAC2 activity was expressed as the ratio of the absorbance at 450 nm after 15 min of incubation at 37°C.[20]


  Results Top


P-glycoprotein expression at baseline, during remission, and at the time of steroid resistance

Expression of P-gp mRNA was significantly lower in individuals (n = 24) who achieved remission at 6-week of steroid therapy as compared to baseline and those who were resistant (n = 7) to steroids [Figure 1]. In addition, P-gp expression was significantly increased in SRNS group as compared to SSNS group after 6 weeks of steroid therapy (P < 0.005).
Figure 1: mRNA gene expression of P-glycoprotein. The first bar represents the P-glycoprotein expression of all the patients at baseline. The second bar represents the P-glycoprotein expression in PBMCs of patients who responded with 6 weeks of steroid therapy. The third bar represents the P-glycoprotein expression in PBMCs of patients who did not respond after 6 weeks of steroid therapy. Peripheral blood mononuclear cells were isolated at baseline, during remission and resistant, and the mRNA levels of P-glycoprotein were quantified by real-time polymerase chain reaction technique. The experiments are representative of three independent series. Pooled data of all the experiments are represented as mean ± standard error of the mean. Significant differences compared to control were indicated by P<0.05

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Out of seven steroid-resistant patients, five achieved complete remission following tacrolimus therapy and their P-gp expression and activity were reduced whereas HDAC2 expression was increased [Supplementary Figure 1]a and [Supplementary Figure 1]b. Of the total 24 patients who achieved remission after 6-week steroid therapy, seven relapsed. At relapse, P-gp mRNA expression and activity of these 7 patients were increased, whereas the expression of HDAC2 was decreased [Supplementary Figure 2]a and [Supplementary Figure 2]b.



Histone deacetylase 2 expression at baseline, during remission, and at the time of steroid resistance

The expression of HDAC2 mRNA was significantly higher at baseline and at remission following 6-week steroid therapy as compared to their expression in those who were resistant to steroids [Figure 2]. In addition, HDAC2 mRNA expression was significantly decreased in patients of SRNS as compared to that of SSNS group after 6 weeks of steroid therapy (P < 0.005).
Figure 2: mRNA gene expression of histone deacetylase 2. The first bar represents the histone deacetylase-2 expression of all the patients at baseline. The second bar represents the histone deacetylase-2 expression in PBMCs of patients who responded with 6 weeks of steroid therapy. The third bar represents the histone deacetylase-2 expression in PBMCs of patients who did not respond after 6 weeks of steroid therapy. Peripheral blood mononuclear cells were isolated at baseline, during remission and resistant, and the mRNA levels of histone deacetylase 2 were quantified by real-time polymerase chain reaction technique. The experiments are representative of three independent series. Pooled data of all the experiments are represented as mean ± standard error of the mean. Significant differences compared to control were indicated by P <0.05

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P-glycoprotein functional assay at baseline, during remission, and at the time of resistance to steroids

Similar to the expression of P-gp, the functionality of P-gp was significantly reduced in NS patients who achieved remission after 6-week steroid therapy as compared to baseline (P < 0.005) whereas there was no significant difference in resistant patients as compared to base line (P = 0.37) [Figure 3]. In addition, the P-gp functionality was significantly increased in SRNS group as compared to SSNS group after 6 weeks of steroid therapy (P < 0.005).
Figure 3: P-glycoprotein functional activity. The first bar represents the P-glycoprotein functional activity of all the patients at baseline. The second bar represents the P-glycoprotein functional activity patients who responded with 6 weeks of steroid therapy. The third bar represents the P-glycoprotein functional activity of patients who did not responded after 6 weeks of steroid therapy. Peripheral blood mononuclear cells were isolated at baseline, during remission and resistant, and the functional activity was analyzed by flow cytometry

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Histone deacetylase 2 enzyme activity in steroid-sensitive Nephrotic syndrome and steroid-resistant Nephrotic syndrome patients

The enzymatic activity of HDAC2 was significantly higher in patients of SSNS as compared to that of patients of SRNS at 6-week of steroid therapy (P < 0.005), [Figure 4].
Figure 4: Mean HDAC 2 activity expressions of peripheral blood lymphocytes in the remission as well as resistant group. The histone deacetylase 2 activity was significantly higher in remission group as compared to the resistant group. Significant differences were indicated by P <0.05

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  Discussion Top


In the present study, we longitudinally followed up 31 patients and observed that the P-gp mRNA expression and functional activity was increased at baseline and at steroid resistance as compared during remission state of NS. In addition, HDAC2 mRNA expression was increased at baseline and during remission as compared to that of steroid resistance state of NS patients. The enzymatic activity of HDAC2 was significantly increased in SSNS patients as compared to that of SRNS patients.

During NS, an imbalance between pro-inflammatory cytokines such as Interferon γ, Interleukin-2, Interleukin-4, Interleukin-17 (IL2, IL4, IL17), and anti-inflammatory transforming growth factor-beta 1, IL-10 cytokines, respectively, have been reported to be responsible for inflammatory condition leading to disease phenotype.[8],[23] Majority of the pro-inflammatory cytokines are secreted by T helper cell 1 and T helper cell 17 (Th1, Th17 cells),[23],[24] whereas anti-inflammatory cytokines are secreted by Th2 and regulatory T cells. These cytokines genes are regulated by HDAC2. Reduced HDAC2 levels in COPD and bronchial asthma had been linked with increased expression of pro-inflammatory cytokines genes through nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB)-mediated pathways.[25] Thus, reduced HDAC2 levels may contribute to an increase in pro-inflammatory cytokines milieu, leading to steroid resistance in NS patients. HDAC2-mediated deacetylation of the glucocorticoid receptor enables suppression of NF-κB. Significantly decreased mRNA levels of HDAC2 may contribute to the activation of the inflammatory gene in lupus PBMC, and lupus patients were found to have a positive correlation between HDAC2 mRNA expression levels and disease duration.[26]

P-gp has been linked with steroid resistance in NS patients[8],[11] and SLE patients who did not respond well with steroids and immunosuppressants.[27] The exact mechanism how P-gp is regulated in immune cells are not well understood though it has been observed that interleukin-2 increases P-gp expression on lymphocytes by inducing translocation of YB-1, an important transcriptional factor for MDR-1 gene.[28] There are observations that inhibitor of P-gp is effective in the treatment of patients who initially fail or do not respond to immunosuppressive drugs in psoriatic arthritis, myasthenia gravis, and RA.[29],[30],[31] It has been observed that P-gp is regulated by HDAC2 and they are in reciprocal relationship in NS patients[32] and placental cells.[33] HDAC2 inhibitors are reported to induce P-gp expression.[34],[35] Reduction of bioavailability of steroids due to increased expression and activity of P-gp has been reported in many autoimmune diseases.[9] The exact mechanism of how HDAC2 regulates P-gp is not well understood and warrant further studies. Probable mechanism may be; HDAC2 is involved in transcriptional repression of P-gp, and dissociation of HDAC2 from the promoter region may lead to recruitment of P300, P300/CBP-associated factor and nuclear transcription factor Y to the promoter region via acetylation of SP1 which may result in induction of P-gp.[33]

Steroid is the mainstay of therapy in NS patients; however, more than 20% do not respond to steroid at the outset, and a significant proportion of the responders too develop steroid resistance during later stage of treatment. Tacrolimus has been reported to benefit SRNS patients. Tacrolimus, cyclophosphamide, and mycophenolate mofetil are immunosuppressive drugs that are used to manage these patients who do not respond to steroids. Tacrolimus, not only directly blocks P-gp activity but also decreases the induction of P-gp by IL-2-mediated mechanisms.[36] A number of reports have highlighted that epigenetic changes are important in terms of affecting individual clinical responses to drugs.[18],[37],[38],[39] Both SLE and NS are immune cell-mediated disease, and mRNA expression of HDAC2 has been reported to be significantly decreased in SLE patients,[26] which was in accordance with our study. These observations suggest the importance of epigenetic factors in regulation of immune cell-mediated diseases. The results of the present study are in accordance with the observation of Xu et al., whereby selective knockdown of HDAC1, HDAC2, or combined HDAC1 plus HDAC2 has been reported to increase the expressions of P-gp, Multidrug-Resistant Associated Protein-1 (MRP-1), and MRP-2 in cell lines derived from human colorectal adenocarcinomas (HCT-8 and HCT-116). In addition, overexpression of HDAC1 and HDAC2 significantly reduced the expression of P-gp, MRP-1, and MRP-2 leading to a reversal of multidrug resistance.[40] In another study by Guan et al., HDAC2 expression and enzymatic activity were reduced in SRNS patients as compared to SSNS patients. The advantage of the present study lies in the fact that earlier studies have evaluated expression of HDAC2 and P-gp at one-time point only however we have longitudinally followed up patients till remission[20] and further when they relapsed. It is likely that modulators of P-gp and HDAC2 might be helpful in better management of steroid resistance in immune cell-mediated diseases such as NS and SLE, or RA.


  Conclusion Top


Steroid responsiveness is regulated by the expression and function of P-gp and HDAC2 in childhood NS. The addition of P-gp inhibitor and/or inducers of HDAC2 to steroid therapy have the potential to be explored as adjunctive therapy in NS.

Acknowledgment

Harshit Singh is a registered Ph.D. student from Dr. APJ Abdul Kalam Technical University, Lucknow, Uttar Pradesh, India with Registration number: Ph.D./15/BIOTECH/1737.

Financial support and sponsorship

This work received support from Council of Science and Technology grant, Uttar Pradesh, India (CST/SEPRD/D-5052).

Conflicts of interest

There are no conflicts of interest.



 
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