Effect of uric acid on gentamicin-induced nephrotoxicity in rats - role of matrix metalloproteinases 2 and 9.
In this work, we aimed to study the effect of uric acid on gentamicin-induced nephrotoxicity. Male Sprague-Dawley rats were assigned to one of six groups (six rats each) which received intraperitoneal injections for 9 days: (S) saline; (UA) Uric acid alone; (G) Gentamicin alone; (G + UA) Gentamicin + uric acid; (G rec) Gentamicin recovery and (G + UA rec) Gentamicin + uric acid recovery. In (G rec) and (G + UA rec), rats recovered for 7 days after the last injection. Urine and blood samples were taken on day 0 and at the end of every stage. Kidneys were harvested for histological scoring, determination of renal malondialdehyde (MDA), zymography and western blots for matrix metalloprotease (MMP)-2 and MMP-9. Uric acid alone did not provoke changes in biochemical and histological parameters when compared to controls. Gentamicin alone increased significantly plasma creatinine and blood urea nitrogen and caused a moderate histological damage. When combined with uric acid, these conditions worsened. MMP-9 activity and expression was decreased in rats from group G + UA as compared with rats from group G, while activity of MMP-2 was similarly increased in both groups when compared to controls. The increase in renal MDA induced by gentamicin was not altered when it was combined with uric acid. During the recovery stage, all biochemical parameters returned to normal levels, though a trend for delay of tubular damage recovery was observed in group G + UA rec when compared with group G rec. The results indicate that uric acid worsens gentamicin-induced nephrotoxicity. The mechanism is likely to implicate down-regulation of MMP-9.
Romero
Freddy
F
Centre for Biomedical Investigations, IVIC-Zulia, Maracaibo, Venezuela.
Pérez
Mariela
M
Chávez
Maribel
M
Parra
Gustavo
G
Durante
Paula
P
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D005839:Gentamicins / Q000633:toxicity*; D007668:Kidney / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D007677:Kidney Function Tests; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced / Q000209:etiology / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011507:Proteinuria / Q000139:chemically induced; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000473:pathology; D017392:Thiobarbituric Acid Reactive Substances / Q000737:chemistry; D013997:Time Factors; D014527:Uric Acid / Q000097:blood / Q000494:pharmacology* / Q000652:urine
D000900:Anti-Bacterial Agents; D005839:Gentamicins; D017392:Thiobarbituric Acid Reactive Substances; D014527:Uric Acid; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9