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(American Journal of Pathology. 2000;156:879-888.)
© 2000 American Society for Investigative Pathology

Regular Articles

Lack of Endothelial Nitric Oxide Synthase Aggravates Murine Accelerated Anti-Glomerular Basement Membrane Glomerulonephritis

Peter Heeringa^*, Harry van Goor^§, Yoshie Itoh-Lindstrom, Nobuyo Maeda^*, Ronald J. Falk, Karel J. M. Assmann^¶, Cees G. M. Kallenberg and J. Charles Jennette^*

From the Departments of Pathology and Laboratory Medicine^*
and Medicine,
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; the Departments of Clinical Immunology
and Pathology,^§
University Hospital, Groningen, The Netherlands; and the Department of Pathology,^¶
University Hospital, Nijmegen, The Netherlands

Nitric oxide (NO) radicals generated by endothelial nitric oxide synthase (eNOS) are involved in the regulation of vascular tone. In addition, NO radicals derived from eNOS inhibit platelet aggregation and leukocyte adhesion to the endothelium and, thus, may have anti-inflammatory effects. To study the role of eNOS in renal inflammation, the development of accelerated anti-glomerular basement membrane (GBM) glomerulonephritis was examined in mice lacking a functional gene for eNOS and compared with wild-type (WT) C57BL/B6j mice. WT C57BL/6j mice (n = 12) and eNOS knockout (-/-) mice (n = 12) were immunized intraperitoneally with sheep IgG (0.2 mg in complete Freund’s adjuvant). At day 6.5 after immunization, mice received a single i.v. injection of sheep anti-mouse GBM (1 mg in 200 µl PBS). Mice were sacrificed at day 1 and 10 after induction of the disease. All WT mice survived until day 10, whereas 1 eNOS-/- mouse died and 2 more became moribund, requiring sacrifice. At day 10, eNOS-/- mice had higher levels of blood urea nitrogen than WT mice (P < 0.02), although proteinuria was comparable. Immunofluorescence microscopy documented similar IgG deposition in both WT and eNOS-/- mice, but eNOS-/- mice had more extensive glomerular staining for fibrin at day 10 (P < 0.007). At day 10, light microscopy demonstrated that eNOS-/- mice had more severe glomerular thrombosis (P < 0.003) and influx of neutrophils (P < 0.006), but similar degrees of overall glomerular endocapillary hypercellularity and crescent formation. In conclusion, accelerated anti-GBM glomerulonephritis is severely aggravated in eNOS-/- mice, especially with respect to glomerular capillary thrombosis and neutrophil infiltration. These results indicate that NO radicals generated by eNOS play a protective role during renal inflammation.

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