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1 Department of Nephrology and Center of Cardiovascular Research, Charite University Medicine Berlin, Charite Campus Mitte, Humboldt University, Berlin, Germany
2 Department of Cell Biology and Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
* To whom correspondence should be addressed. E-mail: Harm.Peters{at}charite.de.
Abstract. Tubulointerstitial inflammation and fibrosis are hallmarks of chronic progressive renal diseases. To characterize the functional interaction between cell infiltration and matrix expansion this study compared the immunosuppressant mycophenolate mofetil (MMF), intended as primarily anti-inflammatory intervention, the ACE inhibitor enalapril, intended as primarily anti-fibrotic drug and a combination of both as anticipated anti-inflammatory/anti-fibrotic intervention. The model used was anti-thy1-induced chronic-progressive glomerulosclerosis (cGS) in the rat where a brief anti-thy1-induced glomerular injury progresses spontaneously towards tubulointerstitial fibrosis and renal insufficiency. cGS was induced by injection of anti-thy1 antibody into uni-nephrectomized Wistar rats. One week after disease induction, animals were randomly assigned to the following groups: cGS, cGS plus MMF (20 mg/kg body weight/d), cGS plus high dose of enalapril (12 mg/kg body weight/d), and cGS plus both. At week 16 after disease induction, MMF or enalapril alone reduced signs of chronic renal disease significantly and similarly as compared to the untreated cGS group. Variables measured included proteinuria, blood pressure, tubulointerstitial and glomerular matrix accumulation, expression of transforming growth factor-beta1, fibronectin and plasminogen activator inhibitor-1, infiltration of lymphocytes and macrophages, plasma creatinine and urea levels and GFR. Combined MMF and enalapril treatment was not superior to single therapy. In conclusion, MMF slows the progression of chronic renal fibrosis and renal insufficiency as effectively as high dose enalapril in the antithy1- induced chronic-progressive glomerulosclerosis model. The dual anti-inflammatory/antifi-brotic intervention does not yield additive renoprotective effects, indicating that MMF and enalapril interfere with similar or very closely related pathways involved in progression of renal disease.
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