POLYASPARTIC ACID PROTECTS AGAINST GENTAMICIN-NEPHROTOXICITY IN THE RAT

  • 1 July 1989
    • journal article
    • research article
    • Vol. 250  (1) , 149-153
Abstract
Polyamino acids including polyaspartic acid (PAA) have been reported to provide protection against the development of aminoglycoside-induced nephrotoxicity in the rat as assessed by histopathology scoring. We sought to confirm and extend these observations by determining whether PAA also prevented functional and biochemical lesions of gentamicin-nephrotoxicity in an animal model studied extensively in our laboratory. Rats were given injections of: 1) 0.9% NaCl at 2.5 ml/kg b.wt. per day; 2) PAA (mol.wt. 15,000) at 500 mg/kg per day; 3) gentamicin at 100 mg/kg per day or 4) gentamicin at 100 mg/kg per day and PAA at 500 mg/kg per day for 6 days. Rats injected with gentamicin exhibited: 1) increased urinary excretion of the brush border membrane enzyme alanine aminopeptidase and the lysosomal enzyme N-acetyl-.beta.-d-glucosaminidase after the first injection; 2) increased total phospholipid and malondialdehyde but decreased catalase activity in the renal cortex; 3) elevation of serum creatinine and depression of creatinine clearance and 4) extensive proximal tubular cells necrosis all determined 24 hr after the last injection of gentamicin. Rats injected with gentamicin plus PAA also exhibited increased urinary excretion of alanine aminopeptidase not different in magnitude from that of rats injected with gentamicin alone, whereas N-acetyl-.beta.-d-glucosaminidase rose more slowly and returned to base line by day 4. Total renal cortical phospholipid was elevated to the same extent in the two groups. Malondialdehyde was not different from control and catalase activity was signficantly less depressed in rats injected with gentamicin plus PAA. Furthermore, serum creatinine and creatinine clearance in rats injected with gentamicin plus PAA were not different from the levels of control rat and proximal tubular cell necrosis was markedly reduced compared to rats injected with gentamicin alone. The renal cortical concentration of gentamicin was similar in the two groups. We conclude that the coadministration of PAA with gentamicin affords marked protection against the development of functional, biochemical and histopathological lesions of gentamicin-induced nephrotoxicity in the rat and that the protection is independent of the renal cortical accumulation of drug. This latter observa tion implies that PAA prevents gentamicin from disrupting one or more intracellular processes causally linked to the injury cascade of aminoglycoside toxicity.