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P-Glycoprotein Induction Ameliorates Colistin Induced Nephrotoxicity in Cultured
Human Proximal Tubular Cells
#MMPMID26287374
Lee SH
; Kim JS
; Ravichandran K
; Gil HW
; Song HY
; Hong SY
PLoS One
2015[]; 10
(8
): e0136075
PMID26287374
show ga
The pathogenesis of colistin induced nephrotoxicity is poorly understood.
Currently there are no effective therapeutic or prophylactic agents available.
This study was aimed to determine the mechanism of colistin induced
nephrotoxicity and to determine whether P-glycoprotein (P-gp) induction could
prevent colistin induced nephrotoxicity. Colistin induced cell toxicity in
cultured human proximal tubular cells in both dose and time dependent manner.
Colistin provoked ROS in a dose dependent manner as measured by DCF-DA. To
investigate apoptosis, caspase 3/7 activity was determined. Caspase 3/7 activity
was increased dose dependently (25, 50, 100 ?g/ml) at 6 h. Autophagosome
formation was assessed by measuring LC3- II/LC3-I ratio. The ratio of LC3-II to
LC3- I was increased at 2 h (25 ?g/ml). Suppression of autophagosome formation
increased colistin induced nephrotoxicity. The expression of P-gp and the cell
toxicity was determined in colistin with or without dexamethasone (P-gp inducer)
and verapamil (selective P-gp inhibitor). Colistin itself suppressed the
expression of P-gp. P-gp expression and activity decreased colistin induced
nephrotoxicity with dexamethasone treatment. In addition induced P-gp transporter
was shown to improve the efflux effect on colistin treated HK2 cell line, which
was demonstrated by calcein-AM fluorescence accumulation assay. The increased
activity could be blocked by N-acetylcysteine. In conclusion, colistin induces
nephrotoxicity by suppressing P-gp. Induction of P-gp could ameliorate colistin
induced nephrotoxicity by decreasing apoptosis.
|ATP Binding Cassette Transporter, Subfamily B, Member 1/*biosynthesis
[MESH]
free
free
free
