In vitro mechanisms and models of gentamicin nephrotoxicity.
Nephrotoxicity is the dose limiting feature of gentamicin adminstration. The nephrotoxic potential of gentamicin was investigated in primary cultures of rat renal proximal tubular cells and in the established renal epithelial cell lines, LLC-PK(1) cells and MDCK cells. Polyaspartic acids have been reported to ameliorate the nephrotoxicity of gentamicin in vivo. However, these compounds have been reported to exert other toxic side effects. We investigated the role of magnesium-l-aspartate-hydrochloride in nephroprotection against gentamicin in these models of nephrotoxicity. Gentamicin admistration resulted in a reduction in the DNA and protein content of the primary proximal tubular cells and an impaired calcium uptake into these cells. Magnesium-l-aspartate-hydrochloride significantly reduced the extent of [(3)H]gentamicin binding to these cells. Transepithelial resistance determination in the established renal cell lines revealed that gentamicin disrupted intercellular communications, while magnesium-l-aspartate-hydrochloride abolished this gentamicin-induced alteration. The actions of gentamicin were shown to occur prior to any loss of cell viability as assessed by flow cytometry. It is concluded that these systems provide useful models for the investigation of gentamicin nephrotoxicity and that magnesium-l-aspartate-hydrochloride may be useful in ameliorating gentamicin nephrotoxicity in clinical conditions.
McGlynn
H
H
Department of Pharmacology, University College Dublin, Belfield, Dublin 4, Ireland.
Ryan
M P
MP