Pharmacologic modulators of nitric oxide exacerbate tubulointerstitial inflammation in proteinuric rats

• Published in: Journal of the American Society of Nephrology 2001-08, Vol.12 (8), p.1696-1705
• Main Authors: RANGAN, Gopala K, YIPING WANG, HARRIS, David C. H
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cytokines - genetics; Disease Progression; Glomerulonephritis; Kidney - enzymology; Kidney - physiopathology; Kidney Cortex - metabolism; Kidney Tubules - pathology; Male; Malondialdehyde - metabolism; Medical sciences; Nephritis - pathology; Nephritis - physiopathology; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; NF-kappa B - physiology; Nitric Oxide - physiology; Nitric Oxide Synthase - metabolism; Nitrites - urine; Proteinuria - pathology; Proteinuria - physiopathology; Rats; Rats, Wistar; RNA, Messenger - metabolism
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.v1281696

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.