Pharmacologic modulators of nitric oxide exacerbate tubulointerstitial inflammation in proteinuric rats.
Nitric oxide (NO) regulates inflammatory responses partly by cell-specific inhibition of the transcription factor nuclear factor kappaB (NF-kappaB). This study investigated the effect of continuous oral administration of an NO donor (molsidomine [Mol]), NO precursor (L-arginine [L-arg]), or selective inhibitors of inducible NO synthase (iNOS; aminoguanidine [AG], L-N(6)-(1-iminoethyl)lysine [L-NIL]) on the progression of tubulointerstitial inflammation and NF-kappaB activation in a non-immune model of chronic glomerular disease (Adriamycin nephropathy [AN]), from day 8 until day 30 after disease induction. On day 30, rats with AN had heavy proteinuria, reduced creatinine clearance, and tubulointerstitial disease. Treatment with both AG and L-NIL exacerbated the progression of AN as evidenced by (1) increased renal cortical malondialdehyde; (2) reduced creatinine clearance; and (3) increased tubular atrophy, interstitial volume, and monocyte infiltration. Unexpectedly, Mol also increased renal malondialdehyde and worsened tubular injury, whereas L-arg had no effect. The increase in renal cortical NF-kappaB activation in AN was not altered by AG, L-NIL, or Mol, but the mRNA expression of monocyte chemoattractant protein-1, interleukin-10, and osteopontin were elevated in these groups. Nitrite release from kidney slices reduced in AN. Treatment with Mol restored renal nitrite release to normal, whereas neither L-arg nor the NOS inhibitors had an effect. It is concluded that endogenous iNOS-derived NO has a protective role against tubulointerstitial injury and cytokine production in AN. However, the pro-oxidant activity of NO donors may limit their potential benefit in proteinuric renal disease.
Rangan
Gopala K
GK
Renal Unit, Fremantle Hospital, Fremantle, Australia.|Department of Pharmacology, University of Western Australia, Perth, Australia.
Wang
Yiping
Y
Department of Renal Medicine, University of Sydney at Westmead Hospital, Westmead, Sydney, Australia.
Harris
David C H
DCH
Department of Renal Medicine, University of Sydney at Westmead Hospital, Westmead, Sydney, Australia.
D000818:Animals; D016207:Cytokines / Q000235:genetics; D018450:Disease Progression; D007668:Kidney / Q000201:enzymology / Q000503:physiopathology; D007672:Kidney Cortex / Q000378:metabolism; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D009393:Nephritis / Q000473:pathology* / Q000503:physiopathology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009573:Nitrites / Q000652:urine; D011507:Proteinuria / Q000473:pathology* / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D016207:Cytokines; D016328:NF-kappa B; D009573:Nitrites; D012333:RNA, Messenger; D009569:Nitric Oxide; D008315:Malondialdehyde; D019001:Nitric Oxide Synthase