Aminoglycosides are a widely used class of antibiotics. They are commonly prescribed for the treatment and prevention of gram-negative bacterial infection. Although very effective, they can also induce well known toxic side effects. These effects are primarily expressed as damage to the kidney and inner ear, nephro- and ototoxicity, respectively. If administration is terminated the kidney rapidly recovers, however, damage arising in the inner ear can be irreversible. Due to the wide spread and common use of these antibiotics, this toxicity represents a significant clinical and financial burden on the health care system. Inhibition of many cellular processes has been described, but characterization of a specific mechanism has remained elusive. The long term goal of this application is to better characterize the mechanism of aminoglycoside-induced nephrotoxicity. Recent evidence suggests that components involved in inducing endocytosis and fusion of endocytic vesicles, specifically the proteins Rab5 and phosphatidylinositol-3-kinase (PI-3-K), may play a role in aminoglycoside toxicity. Disruption of these processes by inhibition of these 2 proteins' activity could lead to the toxicity that is seen with prolonged aminoglycoside treatment. These proposed studies are designed to look at levels (Rab5), subcellular localization (Rab5), and the activity (Rab5 and PI-3-K) of these proteins in a well characterized rat model of aminoglycoside-induced nephrotoxicity. The rat model of aminoglycoside-induced nephrotoxicity is very similar to the human situation and has been very successfully used as an in vivo model of human toxicity. Rats will be injected with gentimicin (the most commonly used aminoglycoside) for short- (3 days) and long term (18 days) periods. The day following the last injection, effects of gentamicin treatment on the parameters mentioned above will be characterized using morphological and biochemical techniques. By performing these studies, it is hoped that formulation of specific therapies to delay and/or inhibit this toxicity will become possible.
| Girton, Richard A; Sundin, David P; Rosenberg, Mark E (2002) Clusterin protects renal tubular epithelial cells from gentamicin-mediated cytotoxicity. Am J Physiol Renal Physiol 282:F703-9 |
| Sundin, D P; Sandoval, R; Molitoris, B A (2001) Gentamicin inhibits renal protein and phospholipid metabolism in rats: implications involving intracellular trafficking. J Am Soc Nephrol 12:114-23 |
