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The Attenuation of Aminoglycoside‐Induced Renal Cellular Toxicity by Lithium and by Calcium‐Sensing Receptor Antagonism
Author(s) -
MaldonadoPerez David,
Shah Amish,
Stirling Tim,
Ward Donald,
Riccardi Daniela
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a341-a
Subject(s) - antagonism , aminoglycoside , pharmacology , calcium , calcium sensing receptor , toxicity , attenuation , chemistry , lithium (medication) , receptor , medicine , calcium metabolism , antibiotics , biochemistry , physics , optics
We have shown previously, that aminoglycosides (AGAs) induce cell death in proximal tubule‐derived opossum kidney (OK) cells and calcium‐sensing receptor (CaR) ‐transfected HEK‐293 (CaR‐HEK) cells. Here we show that when OK cells were cotreated with a CaR antagonist (the calcilytic NPS‐89636, 500 nM), significant attenuation (−77%, n=7, p<0.05) of this toxicity was observed. In CaR‐HEK cells, calcilytic cotreatment ablated gentamicin‐induced cell death. Previous studies in rats have suggested a protective effect of LiCl on gentamicin nephrotoxicity and so to determine whether LiCl acts directly on renal cells, we studied gentamicin‐induced cell death in both OK and CaR‐HEK cells in the presence or absence of LiCl (1mM; 4 days). LiCl cotreatment ablated the rise in cell death but did not reduce the cellular uptake of texas red conjugated gentamicin when assessed by confocal microscopy and a fluorometric assay (n=3, p>0.05). Chronic treatment of CaR‐HEK cells with gentamicin (50 μM for 6 days) resulted in intracellular calcium (Ca 2+ i ) spikes in 47.8 % of cells. In contrast, in the presence of LiCl 1mM, only 6.1 % of cells showed calcium spikes (n=6, p<0.05). In addition, NPS‐89636 completely abolished the calcium spikes induced by gentamicin (n=3, p<0.001), indicating that the AGA effect here is CaR‐mediated. Together, these data demonstrate that CaR antagonism and Li cotreatment inhibit gentamicin‐induced cellular death and that this may occur via attenuation of AGA‐induced in Ca 2+ i mobilization. Grants from Kidney Research UK, BBSRC and Wellcome Trust supported this work.