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Expression of P-glycoprotein in lymphocytes of children with nephrotic syndrome treated with glucocorticoids

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Abstract

Introduction

Glucocorticoids are still the mainstay of therapy for nephrotic syndrome (NS) in children. Poor response to glucocorticoids may relate, in part, to the overexpression of P-glycoprotein (P-gp). The aim of the present study was to determine the expression of P-gp in lymphocytes (CD3) in the peripheral blood of children with steroid-sensitive nephrotic syndrome in the dynamics of the disease. The study group (I) consisted of 18 children, median age 5.75 years, with steroid-sensitive nephrotic syndrome, in whom the examinations were carried out three times: (A) before treatment, during relapse; (B) after 3–4 weeks of prednisone treatment; (C) 2 months after finishing prednisone treatment. The control group (II) consisted of 18 healthy children of the same age. P-gp expression in CD3 lymphocytes of peripheral blood was measured using flow cytometry. During NS relapse and prior to glucocorticoid administration, the CD3/P-gp level was higher (median 3.20%, range 0.80–7.80%) when compared to healthy controls (1.10%, range 0.30– 2.20%) (p<0.01). During glucocorticoid treatment, CD3/P-gp increased significantly and was much higher than in the control group (p<0.01) and in the NS children before treatment (p<0.01). In remission, the P-gp expression decreased, but did not achieve the values of the controls (p<0.05). Fourteen out of eighteen (14/18) children still showed P-gp values above the cut-off level. We also found a positive correlation between the P-gp expression and total prednisone dose in the NS children in all examinations: A: (r=0.540, p<0.05); B: (r=0.630, p<0.01); C: (r=0.653, p<0.01).

Conclusion

In conclusion, the overexpression of P-gp in remission, after finishing glucocorticoid treatment, may indicate that P-gp plays a role in the response to corticosteroids in nephrotic children.

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References

  1. Aicardi G, Benso L, Vignolo M, Terragna A, Verrina E, Cordone G, Coppo R, Sernia O, Sardella ML, Di Battista E (1993) Dose-dependent effects of deflazacort and prednisone on growth and skeletal maturation. Br J Rheumatol 32(Suppl 2):39–43

    PubMed  Google Scholar 

  2. Bourgeois S, Gruol DJ, Newby RF, Rajah FM (1993) Expression of an mdr gene is associated with a new form of resistance to dexamethasone-induced apoptosis. Mol Endocrinol 7(7):840–851

    Article  PubMed  CAS  Google Scholar 

  3. Clark AG, Barratt TM (1998) Steroid-responsive nephrotic syndrome. In: Barratt TM, Avner ED, Harmon WE (eds) Pediatric nephrology, 4th edn. Lippincott Williams & Wilkins, Baltimore, Maryland, pp 731–747

    Google Scholar 

  4. Diaz-Borjon A, Richaud-Patin Y, Alvarado de la Barrera C, Jakez-Ocampo J, Ruiz-Arguelles A, Llorente L (2000) Multidrug resistance-1 (MDR-1) in rheumatic autoimmune disorders. Part II: increased P-glycoprotein activity in lymphocytes from systemic lupus erythematosus patients might affect steroid requirements for disease control. Joint Bone Spine 67(1):40–48

    PubMed  CAS  Google Scholar 

  5. Drach J, Gsur A, Hamilton G, Zhao S, Angerler J, Fiegl M, Zojer N, Raderer M, Haberl I, Andreeff M, Huber H (1996) Involvement of P-glycoprotein in the transmembrane transport of interleukin-2 (IL-2), IL-4, and interferon-gamma in normal human T lymphocytes. Blood 88(5):1747–1754

    PubMed  CAS  Google Scholar 

  6. Ehrich JH, Brodehl J (1993) Long versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Arbeitsgemeinschaft fur Padiatrische Nephrologie. Eur J Pediatr 152(4):357–361

    Article  PubMed  CAS  Google Scholar 

  7. Farrell RJ, Kelleher D (2003) Glucocorticoid resistance in inflammatory bowel disease. J Endocrinol 178(3):339–346

    Article  PubMed  CAS  Google Scholar 

  8. Gottesman MM, Pastan I (1993) Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 62:385–427

    Article  PubMed  CAS  Google Scholar 

  9. Hafezi-Moghadam A, Simoncini T, Yang Z, Limbourg FP, Plumier JC, Rebsamen MC, Hsieh CM, Chui DS, Thomas KL, Prorock AJ, Laubach VE, Moskowitz MA, French BA, Ley K, Liao JK (2002) Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med 8(5):473–479

    Article  PubMed  CAS  Google Scholar 

  10. Hebbar PB, Archer TK (2003) Chromatin remodeling by nuclear receptors. Chromosoma 111(8):495–504

    PubMed  Google Scholar 

  11. Hogg RJ, Portman RJ, Milliner D, Lemley KV, Eddy A, Ingelfinger J (2000) Evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at the National Kidney Foundation conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE). Pediatrics 105(6):1242–1249

    Article  PubMed  CAS  Google Scholar 

  12. Jorgensen C, Sun R, Rossi JF, Costes J, Richard D, Bologna C, Sany J (1995) Expression of a multidrug resistance gene in human rheumatoid synovium. Rheumatol Int 15(2):83–86

    Article  PubMed  CAS  Google Scholar 

  13. Lee CG, Gottesman MM (1998) HIV-1 protease inhibitors and the MDR1 multidrug transporter. J Clin Invest 101(2):287–288

    Article  PubMed  CAS  Google Scholar 

  14. Levy AS, Cunningham-Rundles S, Mazza B, Simm M, Gorlick R, Bussel J (2002) High P-glycoprotein-mediated export observed in patients with a history of idiopathic thrombocytopenic purpura. Br J Haematol 118(3):836–838

    Article  PubMed  CAS  Google Scholar 

  15. Maillefert JF, Maynadie M, Tebib JG, Aho S, Walker P, Chatard C, Dulieu V, Bouvier M, Carli PM, Tavernier C (1996) Expression of the multidrug resistance glycoprotein 170 in the peripheral blood lymphocytes of rheumatoid arthritis patients. The percentage of lymphocytes expressing glycoprotein 170 is increased in patients treated with prednisolone. Br J Rheumatol 35(3):430–435

    PubMed  CAS  Google Scholar 

  16. McKay LI, Cidlowski JA (1999) Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr Rev 20(4):435–459

    Article  PubMed  CAS  Google Scholar 

  17. Meijer OC, de Lange EC, Breimer DD, de Boer AG, Workel JO, de Kloet ER (1998) Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. Endocrinology 139(4):1789–1793

    Article  PubMed  CAS  Google Scholar 

  18. Montano E, Schmitz M, Blaser K, Simon HU (1996) P-glycoprotein expression in circulating blood leukocytes of patients with steroid-resistant asthma. J Investig Allergol Clin Immunol 6(1):14–21

    PubMed  CAS  Google Scholar 

  19. (1981) The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr 98(4):561–564

  20. Tsuruo T (1993) Reversal of acquired resistance to vinca alkaloids and anthracycline antibiotics. Cancer Treat Rep 67(10):889–894

    Google Scholar 

  21. Ueda K, Cardarelli C, Gottesman MM, Pastan I (1987) Expression of a full-length cDNA for the human “MDR1” gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc Natl Acad Sci USA 84(9):3004–3008

    Article  PubMed  CAS  Google Scholar 

  22. Ueda K, Okamura N, Hirai M, Tanigawara Y, Saeki T, Kioka N, Komano T, Hori R (1992) Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone. J Biol Chem 267(34):24248–24252

    PubMed  CAS  Google Scholar 

  23. Wacher VJ, Wu CY, Benet LZ (1995) Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 13(3):129–134

    PubMed  CAS  Google Scholar 

  24. Wasilewska A, Zoch-Zwierz W (2005) Expression of glucocorticoid receptors in nephrotic children depending on total prednisone dose. J Pediatr Endocrinol Metab 18(8):799–806

    PubMed  CAS  Google Scholar 

  25. Wasilewska A, Zoch-Zwierz W, Tomaszewska B, Wiercinski R, Stasiak-Barmuta A (2003) Expression of glucocorticoid receptors in mononuclear cells in nephrotic syndrome. Pediatr Nephrol 18(8):778–782

    Article  PubMed  Google Scholar 

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Correspondence to Anna M. Wasilewska.

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Wasilewska, A.M., Zoch-Zwierz, W.M. & Pietruczuk, M. Expression of P-glycoprotein in lymphocytes of children with nephrotic syndrome treated with glucocorticoids. Eur J Pediatr 165, 839–844 (2006). https://doi.org/10.1007/s00431-006-0177-1

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