Forefronts In Nephrology: Nitric Oxide And Inflammation
Kidney International (2002) 61, 826–833; doi:10.1046/j.1523-1755.2002.00228.x
Nitric oxide synthase isoform expression in acute versus chronic anti-Thy 1 nephritis
Markus Ketteler1, Ralf Westenfeld1, Alexander Gawlik, Sebastian Bachmann, Alexander Frey, Gilbert Schönfelder, Martin Paul, Armin Distler and Emile De Heer
Department of Medicine II, University Hospital Aachen, Departments of Medicine IV and Clinical Pharmacology and Toxicology, University Hospital Benjamin Franklin, Free University of Berlin, and Institute of Anatomy, Humboldt-University of Berlin, Berlin, Germany; and Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
Correspondence: Markus Ketteler, M.D., Department of Medicine II, University Hospital Aachen, Pauwelsstra
e 30 D-52057 Aachen, Germany. E-mail: mketteler@ukaachen.de
1Both authors contributed equally to the work done in this study.
Abstract
Nitric oxide synthase isoform expression in acute versus chronic anti-Thy 1 nephritis.
Background
Two inbred Lewis rat substrains (LEW/Moe, LEW/Maa) were identified responding differently to induction of anti-Thy 1 glomerulonephritis (aThy 1-GN). LEW/Moe rats show an acute mesangioproliferative glomerulonephritis with rapid healing of glomerular lesions within four weeks, while LEW/Maa rats develop severe glomerular injury followed by chronic glomerular sclerosis and persistent albuminuria. We investigated whether the glomerular expression pattern of nitric oxide synthase (NOS) isoforms could explain these substrain-related differences.
Methods
Rats (N = 5 to 7 per group) were investigated in a time course experiment. Severity of aThy 1-GN was determined by albuminuria measurements, glomerular matrix score and microaneurysm formation. Glomerular gene expression of NOS isoforms was determined by semiquantitative RT-PCR. Inducible NOS (iNOS) activity was determined in cultured glomeruli and peritoneal macrophages. Neuronal NOS (nNOS) protein expression was detected by Western blotting and enzyme histochemistry. Plasma renin activity (PRA) was measured by RIA.
Results
Induction of iNOS expression and activity was found significantly increased and sustained in LEW/Maa vs. LEW/Moe rats associated with an increased number of infiltrating macrophages and with an increased capacity of iNOS-expression and iNOS-activation by isolated macrophages in LEW/Maa rats. Glomerular nNOS mRNA and nNOS protein expression were constitutively increased in LEW/Maa rats. Renal nNOS localization was restricted to the macula densa region in both substrains and associated with increased PRA in LEW/Maa rats. No difference in glomerular endothelial NOS-mRNA expression between the substrains was observed.
Conclusions
Increased glomerular iNOS and nNOS expression were associated with chronic anti-Thy 1 glomerulonephritis in LEW/Maa rats and may contribute to glomerular damage by separate mechanisms.
Keywords:
macrophages, albuminuria, plasma renin activity, endothelial nitric oxide synthase, mesangioproliferative glomerulonephritis
