Angiotensin-converting enzyme inhibition but not beta-adrenergic blockade limits transforming growth factor-beta overexpression in acute normotensive anti-thy1 glomerulonephritis.
OBJECTIVE
Recent experimental studies in chronic kidney disease have suggested that sympathicolytic drugs, similar to angiotensin II antagonism, limit renal fibrosis independent of blood pressure control. Using the model of acute and normotensive anti-thy1 glomerulonephritis, we analysed the action of beta-adrenergic blockade (as compared with angiotensin-converting enzyme inhibition) on renal overexpression of the profibrotic cytokine transforming growth factor (TGF)-beta.


METHODS
One day after induction of anti-thy1 glomerulonephritis, rats were given increasing doses of the beta-blockers metoprolol or nebivolol (0.1-fold, one-fold, 10-fold and 20-fold of the known blood pressure dose) until day 6 and the 20-fold dose until day 12. Additional animals were treated with a high dose of the angiotensin-converting enzyme inhibitor enalapril. At the end of each experiment, blood pressure and heart rate were recorded, glomerular matrix expansion was scored histologically, and protein expression of TGF-beta(1), fibronectin and plasminogen activator inhibitor-1 was determined in the supernatant of cultured glomeruli.


RESULTS
Metoprolol and nebivolol reduced heart rate in a dose-dependent manner. Blood pressure was normal in untreated animals and not significantly affected by either treatment. Compared with untreated nephritic rats, TGF-beta(1) overexpression was not significantly changed by metoprolol or nebivolol in any dose or treatment period. In contrast, TGF-beta(1) levels were significantly reduced by enalapril both 6 and 12 days after disease induction (-52 and -63%, respectively). The changes in glomerular matrix score, fibronectin and plasminogen activator inhibitor-1 production closely followed expression of TGF-beta(1).


CONCLUSIONS
In a model of acute and normotensive glomerular fibrosis, beta-adrenergic antagonism does not reduce TGF-beta overexpression, suggesting that its pressure-independent antifibrotic action may be limited to chronic renal diseases. The beneficial effect of angiotensin II inhibition even on acute matrix expansion may be a relevant mechanism as to the explanation of its superiority in treating fibrotic renal diseases.
Peters
Harm
H
Division of Nephrology, Charité, Campus Mitte, Humboldt-University, Berlin, Germany. Harm.Peters@charite.de
Rückert
Matthias
M
Gaedeke
Jens
J
Liefeldt
Lutz
L
Ketteler
Markus
M
Sharma
Arya M
AM
Neumayer
Hans-H
HH
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D015415:Biomarkers; D001794:Blood Pressure; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004656:Enalapril / Q000494:pharmacology*; D004983:Ethanolamines / Q000494:pharmacology; D005355:Fibrosis; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate; D007518:Isoantibodies; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D000068577:Nebivolol; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001578:Benzopyrans; D015415:Biomarkers; D004983:Ethanolamines; D007518:Isoantibodies; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C035678:anti-Thy antibody; D000068577:Nebivolol; D004656:Enalapril; D008790:Metoprolol