Chronic nitric oxide synthase inhibition aggravates glomerular injury in rats with subtotal nephrectomy

• Published in: Journal of the American Society of Nephrology 1995-01, Vol.5 (7), p.1498-1507
• Main Authors: Fujihara, C K, De Nucci, G, Zatz, R
• Format: Article
• Language: English
• Subjects: Amino Acid Oxidoreductases - antagonists & inhibitors; Angiotensin Receptor Antagonists; Animals; Arginine - analogs & derivatives; Arginine - pharmacology; Biphenyl Compounds - pharmacology; Glomerulosclerosis, Focal Segmental - etiology; Glomerulosclerosis, Focal Segmental - pathology; Hemodynamics; Hypertrophy; Imidazoles - pharmacology; Kidney - pathology; Kidney Glomerulus - pathology; Losartan; Male; Nephrectomy - methods; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Wistar; Renal Circulation; Tetrazoles - pharmacology; Time Factors
• ISSN: 1046-6673
• DOI: 10.1681/ASN.V571498

Besides its glomerular hemodynamic effects, nitric oxide (NO) inhibits platelet aggregation and mesangial cell proliferation, two mechanisms possibly involved in the pathogenesis of glomerulosclerosis (GS). Chronic NO synthase inhibition in the rat leads to marked arterial hypertension and promotes glomerular and interstitial injury, but only mild GS. In this study, NO synthase blockade by nitro-L-arginine methyl ester (L-NAME) was associated with 5/6 nephrectomy, a well-known model of GS. Sixty-eight adult male Munich-Wistar rats were distributed among four groups: SHAM (no renal ablation or drug treatment), NX (5/6 nephrectomy), NX+NAME (5/6 nephrectomy and chronic treatment with L-NAME, 5 mg/dL in drinking water) and NX+NAME+L (as in group NX+NAME but also receiving the angiotensin II receptor inhibitor Losartan potassium (L), 25 mg/dL in drinking water). One week after ablation, rats of Group NX showed moderate glomerular hypertension and hypertrophy. Although glomerular enlargement was also modest in Group NX+NAME, glomerular hypertension was particularly severe in this group. Both alterations were absent in Group NX+NAME+L. Only incipient glomerular and interstitial injury occurred at this phase. Three weeks after ablation, renal structural injury was still modest in Group NX. By contrast, Group NX+NAME exhibited marked GS, glomerular ischemic injury, interstitial expansion, and creatinine retention. Renal injury was largely prevented in Group NX+NAME+L. Tuft enlargement occurred in all groups but was most prominent in Group NX. NO synthase inhibition aggravates parenchymal injury and functional impairment in the remanent kidney by mechanisms that may involve glomerular hypertension and renin-angiotensin activation but that appear to be unrelated to glomerular enlargement.