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.
Similar content being viewed by others
References
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
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
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
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
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
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
Farrell RJ, Kelleher D (2003) Glucocorticoid resistance in inflammatory bowel disease. J Endocrinol 178(3):339–346
Gottesman MM, Pastan I (1993) Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 62:385–427
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
Hebbar PB, Archer TK (2003) Chromatin remodeling by nuclear receptors. Chromosoma 111(8):495–504
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
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
Lee CG, Gottesman MM (1998) HIV-1 protease inhibitors and the MDR1 multidrug transporter. J Clin Invest 101(2):287–288
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
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
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
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
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
(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
Tsuruo T (1993) Reversal of acquired resistance to vinca alkaloids and anthracycline antibiotics. Cancer Treat Rep 67(10):889–894
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
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
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
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
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
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00431-006-0177-1