P-Glycoprotein Induction Ameliorates Colistin Induced Nephrotoxicity in Cultured Human Proximal Tubular Cells

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 μg/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 μg/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.

[1]  Sudhir V. Shah,et al.  Autophagy in acute kidney injury. , 2016, Kidney international.

[2]  J. Li,et al.  Imaging the distribution of polymyxins in the kidney. , 2015, The Journal of antimicrobial chemotherapy.

[3]  M. Rosengart,et al.  CaMKIV-Dependent Preservation of mTOR Expression Is Required for Autophagy during Lipopolysaccharide-Induced Inflammation and Acute Kidney Injury , 2014, The Journal of Immunology.

[4]  Jichang Li,et al.  Colistin-Induced Nephrotoxicity in Mice Involves the Mitochondrial, Death Receptor, and Endoplasmic Reticulum Pathways , 2014, Antimicrobial Agents and Chemotherapy.

[5]  V. Tam,et al.  In Vitro Assessment and Multicenter Cohort Study of Comparative Nephrotoxicity Rates Associated with Colistimethate versus Polymyxin B Therapy , 2014, Antimicrobial Agents and Chemotherapy.

[6]  Kyung-A Kwak,et al.  Indoxyl sulfate promotes apoptosis in cultured osteoblast cells , 2013, BMC Pharmacology and Toxicology.

[7]  Cheng-Tien Wu,et al.  Protective Role of AMP-Activated Protein Kinase-Evoked Autophagy on an In Vitro Model of Ischemia/Reperfusion-Induced Renal Tubular Cell Injury , 2013, PloS one.

[8]  Michael T. Eadon,et al.  Cell cycle arrest in a model of colistin nephrotoxicity. , 2013, Physiological genomics.

[9]  Zohra Ghlissi,et al.  Evaluation of colistin nephrotoxicity administered at different doses in the rat model , 2013, Renal failure.

[10]  J. Li,et al.  Ascorbic acid protects against the nephrotoxicity and apoptosis caused by colistin and affects its pharmacokinetics. , 2012, The Journal of antimicrobial chemotherapy.

[11]  Jian Li,et al.  Melatonin Attenuates Colistin-Induced Nephrotoxicity in Rats , 2011, Antimicrobial Agents and Chemotherapy.

[12]  Tae Hyong Kim,et al.  Early Acute Kidney Injury Is a Risk Factor That Predicts Mortality in Patients Treated with Colistin , 2010, Nephron Clinical Practice.

[13]  Ling Li,et al.  Autophagy is a component of epithelial cell fate in obstructive uropathy. , 2010, The American journal of pathology.

[14]  J. Turnidge,et al.  Renal Disposition of Colistin in the Isolated Perfused Rat Kidney , 2009, Antimicrobial Agents and Chemotherapy.

[15]  Sudhir V. Shah,et al.  Autophagy is associated with apoptosis in cisplatin injury to renal tubular epithelial cells. , 2008, American journal of physiology. Renal physiology.

[16]  C. Thompson,et al.  Autophagy: basic principles and relevance to disease. , 2008, Annual review of pathology.

[17]  Guido Kroemer,et al.  Self-eating and self-killing: crosstalk between autophagy and apoptosis , 2007, Nature Reviews Molecular Cell Biology.

[18]  J. Turnidge,et al.  Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. , 2006, The Lancet. Infectious diseases.

[19]  Phillip J. Bergen,et al.  Colistin Methanesulfonate Is an Inactive Prodrug of Colistin against Pseudomonas aeruginosa , 2006, Antimicrobial Agents and Chemotherapy.

[20]  M. Falagas,et al.  Toxicity of polymyxins: a systematic review of the evidence from old and recent studies , 2006, Critical care.

[21]  Junying Yuan,et al.  Autophagy in cell death: an innocent convict? , 2005, The Journal of clinical investigation.

[22]  S. Cole,et al.  Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. , 2005, Toxicology and applied pharmacology.

[23]  E. Chieli,et al.  Influence of different chemicals on MDR-1 P-glycoprotein expression and activity in the HK-2 proximal tubular cell line. , 2002, Toxicology and applied pharmacology.

[24]  H. Melhus,et al.  Correlation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayers. , 2001, The Journal of pharmacology and experimental therapeutics.

[25]  R. Béliveau,et al.  Dexamethasone modulation of multidrug transporters in normal tissues , 1999, FEBS letters.

[26]  M. Aguilar,et al.  P Glycoprotein: A New Mechanism to Control Drug-Induced Nephrotoxicity , 1998, Nephron Experimental Nephrology.

[27]  E. Ozyilmaz,et al.  Could nephrotoxicity due to colistin be ameliorated with the use of N-acetylcysteine? , 2010, Intensive Care Medicine.

[28]  Devrim Gozuacik,et al.  Autophagy and cell death. , 2007, Current topics in developmental biology.

[29]  T. Hollister,et al.  A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. , 2001, Cancer research.

[30]  I. Pastan,et al.  Biochemistry of multidrug resistance mediated by the multidrug transporter. , 1993, Annual review of biochemistry.