Selective inhibition of inducible nitric oxide synthase enhances intraglomerular coagulation in chronic anti-Thy 1 nephritis.
BACKGROUND
A particular Lewis rat substrain (LEW/Maa) develops chronic glomerulonephritis in the anti-Thy 1 model (aThy 1-GN) characterized by increased microaneurysm formation, chronic glomerular sclerosis and persistent albuminuria. This phenotype is accompanied by increased and prolonged glomerular induction of inducible nitric oxide synthase (iNOS) when compared to the LEW/Moe substrain, in which aThy 1-GN resolves quickly. We investigated the effect of selective iNOS inhibition by l-N6-(1-iminoethyl)-lysine (L-NIL) administration on aThy 1-GN in LEW/Maa rats.


METHODS
Nephritic rats were studied over a period of 7 days. L-NIL-treated animals received 20 mg/day L-NIL in the drinking water starting two days prior to disease induction. iNOS activity was determined in cultured glomeruli and in urine samples, respectively. Severity of aThy 1-GN was determined by scoring glomerular matrix expansion and microaneurysm formation, and by albuminuria measurements (ELISA). Immunohistochemical evaluation was performed including staining for macrophages (ED-1), platelets (PL-1) and fibrin deposition.


RESULTS
L-NIL treated rats (+NIL) showed a significant decrease in peak nitrate production by ex vivo cultured glomeruli, and in urinary nitrate excretion versus untreated nephritic rats (-NIL). Mean arterial pressure remained unchanged in both +NIL and -NIL rats. +NIL rats developed significantly increased albuminuria (+44%) associated with a significant increase in glomerular platelet (+45%) and fibrin deposition (+48%).


CONCLUSIONS
Selective inhibition of iNOS aggravated albuminuria in chronic aThy 1-GN in LEW/Maa rats. Induction of iNOS during the inflammatory phase of this model may be a partially protective mechanism by interfering with intraglomerular coagulation processes.
Westenfeld
Ralf
R
Department of Medicine II, University Hospital Aachen, Pauwelsstrasse 30, D-52057 Aachen, Germany. Ralf.Westenfeld@rwth-aachen.de
Gawlik
Alexander
A
de Heer
Emile
E
Kitahara
Masashi
M
Abou-Rebyeh
Faikah
F
Floege
Juergen
J
Ketteler
Markus
M
D000419:Albuminuria / Q000652:urine; D000818:Animals; D001792:Blood Platelets / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005337:Fibrin / Q000378:metabolism; D007518:Isoantibodies / Q000276:immunology*; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000503:physiopathology*; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009393:Nephritis / Q000150:complications / Q000276:immunology* / Q000503:physiopathology* / Q000652:urine; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011917:Rats, Inbred Lew; D013927:Thrombosis / Q000209:etiology / Q000473:pathology*
D004791:Enzyme Inhibitors; D007518:Isoantibodies; C090663:N(6)-(1-iminoethyl)lysine; C035678:anti-Thy antibody; D005337:Fibrin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D008239:Lysine