[Resistance to therapy in primary nephrotic syndrome: effect of MDR1 gene activity].
MDR1 gene encodes for a transmembranous glycoprotein, gp-170, which acts as a drug export pump and is also a cyclosporine(CsA)-binding protein. This study aimed at evaluating MDR1 expression in NS sensitive(S) and resistant(R) to therapy (steroids/S/, cyclophosphamide/C/, CsA) patients. Twenty six boys, 13 girls aged 3-8 years were included to the study. MDR1 was analysed using: 1) evaluation of gp-170 activity according to DiC2/3/ [3,3-Diethyloxa-carbocyanine Iodide] by means of flow cytometry and as 2) mRNA expression of MDR1 determined by RT-PCR. The analysis was performed in the lymphocyte subset CD4/CD45RA presenting suppressor-inducer activity. Negative control, Jurkat-T-cell line, not expressing the MDR1 phenotype, was transfected with viral expression vector containing a full-length cDNA for the human MDR1 gene. We found that: in SR-NS the high expression of MDR1 was associated mainly with the suppressor-inducer T-cells (CD45RA+CD4+) and was subsequently enhanced during an ineffective treatment with C and/or CsA. C-R-NS and CsA-R-NS were partially reversible by S- and R-Verapamil; this was in vitro confirmed by inhibition of export pump activity, gp-170. SS-NS, C-S-NS and CsA-S-NS presented the low expression and activity of MDR1 comparing to R-children (p < 0.001) and healthy controls (p < 0.00001). Resistance to therapy in NS patients seems to be resulted from the enhanced expression of MDR1 gene and subsequent high activity of export pump P-gp-170. Calcium channel blockers may reverse the MRD1-related resistance in the therapy of NS. Analysis of MDR1 may help to detect of suspected therapy resistance in NS.
Stachowski
J
J
Kliniki Chorób Dzieci Akademii Medycznej w Poznaniu.
Zanker
C B
CB
Runowski
D
D
Zaniew
M
M
Peszko
A
A
Medyńska
A
A
Zwolińska
D
D
Rogowska-Kalisz
A
A
Hyla-Klekot
L
L
Szprygner
K
K
Weglarska
J
J
Sieniawska
M
M
Musiał
W
W
Maciejewski
J
J
Baldamus
C A
CA
D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D009404:Nephrotic Syndrome / Q000188:drug therapy* / Q000235:genetics*; D013256:Steroids
D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D013256:Steroids; D003520:Cyclophosphamide