Selective inhibition of inducible nitric oxide synthase enhances intraglomerular coagulation in chronic anti-Thy 1 nephritis

• Published in: Kidney international Vol. 61; no. 3; pp. 834 - 838
• Main Authors: Westenfeld, Ralf, Gawlik, Alexander, De Heer, Emile, Kitahara, Masashi, Abou-Rebyeh, Faikah, Floege, Juergen, Ketteler, Markus
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01-03-2002; Nature Publishing; Elsevier Limited
• Subjects: Albuminuria - urine; Animals; Biological and medical sciences; Blood Platelets - pathology; Blood Pressure - drug effects; Chronic Disease; Enzyme Inhibitors - pharmacology; fibrin; Fibrin - metabolism; Glomerulonephritis; Isoantibodies - immunology; Kidney Glomerulus - blood supply; Kidney Glomerulus - physiopathology; L-NIL; Lysine - analogs & derivatives; Lysine - pharmacology; Medical sciences; mesangioproliferative glomerulonephritis; Nephritis - complications; Nephritis - immunology; Nephritis - physiopathology; Nephritis - urine; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase Type II; platelets; Rats; Rats, Inbred Lew; renoprotection; Thrombosis - etiology; Thrombosis - pathology; renoprotection; L-NIL; glomerulonephritis; fibrin; mesangioproliferative glomerulonephritis; platelets; Kidney disease; Blood coagulation; Animal model; Urinary system disease; Rat; Enzyme; Rodentia; Albumin; Selectivity; Synthase; Renal glomerulus; Vertebrata; Chronic; Mammalia; Animal; Nitric oxide; Inhibition; Mesangial proliferative glomerulonephritis; Comparative study; Proteinuria
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1046/j.1523-1755.2002.00229.x

Selective inhibition of inducible nitric oxide inhibition enhances intraglomerular coagulation in chronic anti-Thy 1 nephritis.
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.
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.
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%).
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.