title: Effect of nephrotoxins on tubulointerstitial injury and NF-kappaB activation in Adriamycin nephropathy.
abstract: In a previous study we found that an episode of acute subclinical nephrotoxicity with gentamicin (G) (but not that induced by another proximal tubular cell nephrotoxin: ferric nitrilotriacetate, FeNTA), paradoxically reduced the progression of renal function and injury in uninephrectomized rats with nephrotic glomerular disease due to Adriamycin nephropathy (AN). Here, we hypothesized that subclinical exposure to G reduces early renal cortical tubulointerstitial inflammation and NF-kappaB activation in AN. To test this hypothesis, male Wistar rats with established AN received either G (10, 40, or 80 mg/kg by daily s.c.i. for 3 days), FeNTA (1.25, 5, or 10 mg/kg by a single i.p.i.), or vehicle (n=8 per group), 13 to 15 days after disease induction. Although G and FeNTA caused acute tubular necrosis in a dose-dependant manner (day 17), only the highest doses (10 mg/kg and 80 mg/kg) produced an acute elevation in the serum creatinine. On day 33, chronic tubulointerstitial inflammation (tubular atrophy, interstitial ED-1+/CD8+ cell accumulation) and NF-kappaB activation were exacerbated only in the groups that caused functional nephrotoxicity. These data suggest that: 1) the protective effect of subclinical G nephrotoxicity in chronic AN does not involve early changes in interstitial inflammation or NF-kappaB activation; and 2) a single episode of G exposure must be accompanied by clinically apparent nephrotoxicity in order to accelerate progression in a nonuremic model of chronic glomerular disease.
authors.affiliation: Department of Renal Medicine and Transplantation, Center for Transplant and Renal Research, Westmead Millennium Institute, The University of Sydney, Westmead Hospital, Westmead, Sydney 2145, Australia. g.rangan@wmi.usyd.edu.au
authors.forename: Gopala K
authors.initials: GK
authors.lastname: Rangan
authors.forename: Yiping
authors.initials: Y
authors.lastname: Wang
authors.forename: Yuet-Ching
authors.initials: YC
authors.lastname: Tay
authors.forename: Jason D
authors.initials: JD
authors.lastname: Coombes
authors.forename: David C H
authors.initials: DC
authors.lastname: Harris
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D005290:Ferric Compounds / Q000494:pharmacology*; D005500:Follow-Up Studies; D005839:Gentamicins / Q000494:pharmacology*; D007150:Immunohistochemistry; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D009395:Nephritis, Interstitial / Q000188:drug therapy* / Q000473:pathology*; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018570:Risk Assessment
chemical_list: D005290:Ferric Compounds; D005839:Gentamicins; D016328:NF-kappa B; D004317:Doxorubicin; D009571:Nitrilotriacetic Acid; C020326:ferric nitrilotriacetate