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Overexpression of P-glycoprotein and MRP-1 are pharmacogenomic biomarkers to determine steroid resistant phenotype in childhood idiopathic nephrotic syndrome

The Pharmacogenomics Journal volume 21, pages 566–573 (2021)Cite this article

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Abstract

Steroid remains the keystone therapy for Idiopathic Nephrotic Syndrome (NS). Besides genetic factors and histological changes, pharmacogenomic factors also affect the steroid response. The upregulation of P-glycoprotein (P-gp) and Multidrug resistance-associated protein 1 (MRP-1) modulate the pharmacokinetics of steroids and may contribute to steroid resistance. Flow-cytometric analysis of P-gp, MRP-1 expression and functional activity on peripheral blood mononuclear cells (PBMCs) was carried out in steroid-sensitive nephrotic syndrome (SSNS) (n = 171, male 103, mean age = 8.54 ± 4.3); and steroid-resistant nephrotic syndrome (SRNS) (n = 83, male 43, mean age = 7.43 ± 4.6) patients. The genotypings of MDR-1 gene were carried out using PCR-RFLP. We observed that the percentage expression of P-gp (10.01 ± 2.09 and 3.79 ± 1.13, p < 0.001); and MRP-1 (15.91 ± 3.99 and 7.40 ± 2.33, p < 0.001) on lymphocyte gated population were significantly higher in SRNS than that of SSNS. The functional activity of P-gp and MRP-1 was also significantly escalated in SRNS as compared to SSNS (68.10 ± 13.35 and 28.93 ± 7.57, p < 0.001); (72.13 ± 8.34 and 31.56 ± 8.65, p < 0.001) respectively. AUC-ROC curve analysis revealed that P-gp and MRP-1 expression with a cut-off value of 7.13% and 9.62% predicted SRNS with the sensitivity of 90% and 80.7%; and specificity 90% and 80%, respectively. Moreover, MDR-1 homozygous mutant TT+AA for G2677T/A (rs2032582) was significantly associated with SRNS (p = 0.025, OR = 2.86 CI = 1.14–7.14). The expression of P-gp (9.68 ± 4.99 v/s 5.88 ± 3.38, p = 0.002) was significantly higher in the patients of homozygous mutant alleles compared to wildtype GG. The increased expression and functionality of P-gp and MRP-1 contribute to steroid resistance, and MDR-1 homozygous mutant G2677T/A promotes steroid resistance by inducing P-gp expression in NS.

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Fig. 1: Expression and function of MRP-1 and P-gp.
Fig. 2: AUC-ROC curve analysis of P-gp and MRP-1.
Fig. 3: P-gp expression in different genotypes.

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Acknowledgements

We acknowledge the research grant of Indian Council of Medical Research for the completion of the project GIA/40/2014-DHR.

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Authors and Affiliations

  1. Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

    Narayan Prasad & Akhilesh Jaiswal

  2. Department of Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

    Harshit Singh, Saurabh Chaturvedi & Vikas Agarwal

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  1. Narayan Prasad
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Correspondence to Narayan Prasad.

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Prasad, N., Singh, H., Jaiswal, A. et al. Overexpression of P-glycoprotein and MRP-1 are pharmacogenomic biomarkers to determine steroid resistant phenotype in childhood idiopathic nephrotic syndrome. Pharmacogenomics J 21, 566–573 (2021). https://doi.org/10.1038/s41397-021-00233-9

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