Acute glomerular upregulation of ornithine decarboxylase is not essential for mesangial cell proliferation and matrix expansion in anti-Thy-1-nephritis.
BACKGROUND
Pathways of L-arginine metabolism including nitric oxide, agmatine and polyamine synthesis are upregulated during glomerular inflammation in experimental glomerulonephritis. In anti-Thy-1-glomerulonephritis L-arginine-deficient diets ameliorate the disease course in this model. However, it is unclear which metabolic pathway is affected by this substrate depletion. Since polyamines are important proproliferative molecules, we studied the effect of specific polyamine synthesis blockade in vivo on mesangial cell proliferation and glomerular fibrosis in this model.


METHODS
Anti-Thy-1-glomerulonephritis was induced in male Sprague-Dawley rats by single-bolus injection of monoclonal ER4-antibodies. Rats were treated with difluoromethylornithine (0.5-2% in the drinking water), a selective inhibitor of the rate-limiting enzyme of polyamine synthesis, ornithine decarboxylase (ODC). Mesangial cell proliferation and matrix expansion were evaluated in PAS-stained kidney tissues. Glomerular TGF-beta and biglycan-mRNA-expression were determined by Northern blot analysis and albuminuria was measured using a competitive ELISA. Data were compared to untreated controls.


RESULTS
Though complete inhibition of ODC activity was achieved at any time point, difluoromethlornithine treatment had no significant effect on albuminuria, glomerular matrix protein expression and mesangial cell count in this model.


CONCLUSIONS
The acute upregulation of glomerular ODC activity above baseline in anti-Thy1-glomerulonephritis is not pathophysiologically important for disease development however, biological effects of available polyamine pools cannot be excluded by our study.
Ketteler
M
M
Department of Endocrinology and Nephrology, University Hospital Benjamin Franklin, Free University of Berlin, Germany and Department of Pathology, University of Leiden, The Netherlands. gmkett@aol.com
Westenfeld
R
R
Gawlik
A
A
de Heer
E
E
Distler
A
A
D000818:Animals; D000911:Antibodies, Monoclonal; D058578:Biglycan; D002455:Cell Division; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000473:pathology; D016326:Extracellular Matrix Proteins; D005920:Glomerular Mesangium / Q000187:drug effects / Q000473:pathology; D005921:Glomerulonephritis / Q000201:enzymology* / Q000209:etiology / Q000473:pathology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009955:Ornithine Decarboxylase / Q000235:genetics* / Q000378:metabolism*; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism; D011509:Proteoglycans / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018800:Thy-1 Antigens; D016212:Transforming Growth Factor beta / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
D000911:Antibodies, Monoclonal; D058578:Biglycan; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D011509:Proteoglycans; D012333:RNA, Messenger; D018800:Thy-1 Antigens; D016212:Transforming Growth Factor beta; D009955:Ornithine Decarboxylase; D000518:Eflornithine