Year : 2020 | Volume
: 15 | Issue : 1 | Page : 1--2
When doing the right thing is wrong – drug efflux pumps in steroid-resistant nephrotic syndrome
Vaidehi R Chowdhary
Associate Professor, Section of Rheumatology, Allergy and Immunology, Yale University School of Medicine,New Haven, Connecticut, USA
Dr. Vaidehi R Chowdhary
S-517, 300 Cedar Street, New Haven, Connecticut 06520-8031
|How to cite this article:|
Chowdhary VR. When doing the right thing is wrong – drug efflux pumps in steroid-resistant nephrotic syndrome.Indian J Rheumatol 2020;15:1-2
|How to cite this URL:|
Chowdhary VR. When doing the right thing is wrong – drug efflux pumps in steroid-resistant nephrotic syndrome. Indian J Rheumatol [serial online] 2020 [cited 2021 Oct 21 ];15:1-2
Available from: https://www.indianjrheumatol.com/text.asp?2020/15/1/1/281583
Idiopathic nephrotic syndrome (INS) is the most common form of childhood nephrotic syndrome (NS) represeting more than 90% of cases between 1 and 10 years of age. The characteristic renal biopsy findings are diffuse foot process effacement on electron microscopy and minimal changes (minimal change disease), focal segmental glomerulosclerosis (FSGS), or mesangial proliferation on light microscopy. Majority of these patients (>90%) respond to steroid therapy and are termed steroid-sensitive NS (SSNS), but 10%–20% may be steroid-resistant NS (SRNS). Resistance to steroid therapy is associated with poor outcomes. In the PodoNet registry of 1354 patients, the 10-year end-stage renal disease-free survival was 92% in those with complete remission versus 43% in poor responders.
Steroid resistance is commonly seen in patients with NS due to single-gene mutations that affect glomerular podocyte differentiation and function. Some of the common mutations associated with SRNS are, NPHS1/NPHS2 genes that encode nephrin and podocin, respectively; PLCE1 gene (also referred to as NPHS3) that encodes phospholipase C epsilon, and WT1 gene encoding the transcription tumor suppressor protein, Wilms' tumor 1. Other less common mutations such as LAMB2 gene and SMARCAL1 result in syndromic SRNS. Histological patterns of FSGS or mesangial nephropathy are most commonly associated with steroid resistance in patients in whom no genetic cause is identified.
Steroid resistance has been associated with lower expression of glucocorticoid receptor (GR) expression in peripheral blood mononuclear cells (PBMCs) and/or expression of drug efflux pumps called multidrug resistance proteins (MRPs) that can lead to decreased bioavailability of steroids., Transport of molecules across the cell membrane is a normal physiological process carried out by membrane proteins called “transporters”, and this process may be “energy-dependent”. Such a group of transporters that bind to and utilize adenosine triphosphate (ATP) as a source of energy to transport biomolecules are termed ATP-binding cassette (ABC) transporters. Certain members of the ABC transporters are particularly efficient in transporting xenobiotics and other molecules out of the cells to protect them from harmful chemicals. However, these transporters can also efficiently pump out certain beneficial molecules (pharmaceutical compounds) from within the cells, thereby preventing these drugs from achieving their intended effects on the cells. Since these transporters confer resistance to drugs by this efflux mechanism, this group of ABC transporters is also referred to as multidrug resistance (MDR) transporters or MDR efflux pumps. The major ABC superfamily transporters involved in MDR development in humans are P-glycoprotein (P-gp/ABCB1), MDR-associated protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2). A role for MDR in treatment failure has been postulated in several diseases such as asthma, ulcerative colitis, rheumatoid arthritis, and systemic lupus.
Another potential mechanism of steroid resistance involves an important enzyme called histone deacetylase 2 (HDAC2). HDAC2 belongs to a group of enzymes that remove acetyl group from lysine residues in histones (allowing DNA to wrap tightly around them) resulting in reduced gene transcription. In addition, HDAC2 deacetylates lysine residue in GR. The steroid, deacetylated GR receptor-ligand complex, is more efficient in suppressing the activities of nuclear factor-kappa B (NF-κB), a transcription factor that regulates the expression of several pro-inflammatory molecules. A reduction in HDAC2 expression and activity has been linked with increased inflammation in chronic obstructive pulmonary disease and bronchial asthma patients. Therefore, with reference to NS, higher HDAC2 activity would translate to more efficient suppression of NF-κB activity resulting in less pro-inflammatory mediators and improvement in kidney functions. Conversely, lower HDAC2 would mean reduced GR deacetylation, higher NF-κB activity, and heightened inflammation leading to poor or no improvement in renal functions.
In this issue of the Indian Journal of Rheumatology, Singh et al. carried out a prospective study to understand the relationship between P-gp, HDAC2 expression, and functionality to steroid responsiveness in INS. Extensive work by this group previously has shown the important role of MDR-1/P-gp in childhood NS and other autoimmune diseases.,,, In a cohort of 216 North Indian children, G2677T/A polymorphism in MDR-1 gene was associated with steroid resistance. G2677T/A and C3435T mutations in MDR-1 gene in different combinations also increased the risk of developing steroid resistance in NS patients. They further examined the expression of HDAC2, P-gp, and MRP-1 in PBMCs of INS patients. A higher expression of P-gp/MRP-1 and a reduced expression of HDAC2 in PBMCs were associated with steroid resistance in NS patients.In vitro experiments showed that inducers of HDAC2, namely theophylline, had a downregulating effect on P-gp/MRP-1, whereas inhibitors of HDAC2, such as Trichostatin A, upregulated the expression of P-gp/MRP-1, suggesting a reciprocal relationship between the two.
In the present study, thirty-one children (mean age: 8.42 ± 3.8 years) with NS were recruited and treated for 6 weeks with oral prednisolone. 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 and steroid resistance as unresponsiveness to 60 mg/m2 body surface area per day of prednisolone therapy for 4 weeks. Twenty-four patients achieved remission and 7 patients had resistant disease. Kidney biopsy in SRNS patients showed histological features of minimal change disease. In PBMCs from patients with SSNS, the expression of P-gp mRNA was lower and HDAC2 was higher compared to baseline and to levels seen with SRNS disease. Similarly, the functionality of P-gp was reduced and the enzymatic activity of HDAC2 was higher in SSNS compared to baseline and to SRNS. Furthermore, patients with SRNS treated with tacrolimus, an immunomodulatory agent with P-gp-suppressive activity, showed a reduction in P-gp expression plus activity and an increase in HDAC2 expression. Of the 24 patients who initially responded to steroids, 7 relapsed. Interestingly, expression and function of P-gp as well as HDAC2 mRNA correlated these changes in this SRNS group. It can be postulated that the higher expression of P-gp and functionality makes less steroid available to the cells.
While this study is informative and provides novel insights in steroid resistance, some questions require further examination. As discussed previously, patients with certain genetic mutations in podocyte proteins may not respond well to steroid and would be helpful to know their prevalence in this group. Pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6 are known to induce the MDR-1/P-gp, and higher P-gp expression at the time of diagnosis, could be due to ongoing inflammation. In this paper, it is important to see the expression and function of P-gp and HDAC2 in each of the groups (SSNS and SRNS) compared to their respective baselines and not pooled together. The low P-gp and high HDAC2 expression and function may be an association seen with steroid responsiveness, and further mechanistic studies are required to demonstrate causation. Nevertheless, the findings are significant and make an interesting case for modulation of HDAC2 or P-gp expression and function across a broad variety of inflammatory and autoimmune diseases.
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