Dose-dependent ameliorating effect of lipoxin A4 on gentamicin-induced nephrotoxicity in rats: The role of TNFα, TGF-β, ICAM-1, and JNK signaling

Gentamicin (GEN) possesses a broad range of antimicrobial effects. However, it belongs to the aminoglycosides, and has the greatest potential for nephrotoxic effect above all other antibiotics from this group. This study aims to evaluate the possible protective effect of lipoxin A4 (LXA4) against GEN-induced nephrotoxicity in rats. Nephrotoxicity was induced in male Wistar rats by injection of GEN (80 mg/kg/day, i.p.) for 6 days starting from day 7 of the experiment. Rats were treated with either LXA4 (10 mu g/kg/day, i.p.) or LXA4 (50 mu g/kg/day, i.p.) for 14 days starting from day 1 of the experiment, along with GEN as the previous schedule. GEN resulted in a significantly elevated renal function in the form of higher serum creatinine and urea levels. Further, GEN induced abnormal renal histopathology including degenerated glomeruli and tubules, with perivascular inflammation and hemorrhage. All of these findings were significantly decreased by the LXA4 administration. Additionally, LXA4 remarkably reduced the increased serum lipid biomarkers. Moreover, LXA4 significantly inhibited the GEN-induced oxidative stress in the kidneys by decreasing the elevated levels of renal malondialdehyde (MDA) and total nitrite while raising the suppressed levels of renal superoxide dismutase (SOD) and serum total anti-oxidant capacity (TAC). LXA4 inhibited the up-regulated inflammatory mediators ICAM-1, TGF beta 1 protein levels, and TNF-alpha protein expression. Finally, LXA4 suppressed the elevated apoptotic mediators; p-JNK and cleaved caspase-3 expression. Our results proved for the first time that LXA4 ameliorated GEN-induced nephrotoxicity through its antioxidant, anti-inflammatory and anti-apoptotic properties.

Automated summary

Lipoxin A4 (LXA4) can ameliorate GEN-induced nephrotoxicity through its antioxidant, anti-inflammatory, and anti-apoptotic effects, reducing renal dysfunction, histopathological changes, and elevated serum lipid biomarkers.