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- Title
Mycophenolate Mofetil Is as Effective as, but not Additive to a High Dose of Enalapril in Experimental Anti-Thy1-Induced, Chronic Renal Fibrosis.
- Authors
Krämer, S.; Loof, T.; Wang, Y.; Martini, S.; Shimizu, F.; Kawachi, H.; Neumayer, H. -H.; Peters, H.
- Abstract
Objective: Tubulointerstitial matrix protein expansion and cell infiltration are hallmarks of chronic renal disease independent of the underlying disorder. The present study compared an anti-inflammatory (using the immunosuppressant mycophenolate mofetil, MMF), an anti-fibrotic (using the ACE inhibitor enalapril) and a combined anti-inflammatory, anti-fibrotic therapeutic intervention on the course of experimental anti-thy1-induced, chronic glomerulosclerosis (cGS). cGS is a rat model of progressive renal fibrosis, in that the initial brief anti-thy1-induced glomerular injury progresses autonomously towards tubulointerstitial fibrosis and renal insufficiency in a not primarily immune-mediated manner. Methods: cGS was induced by injection of anti-thy1 antibody into uni-nephrectomized male Wistar rats. One week after disease induction, animals were randomly assigned to the following groups (n = 8-12 per group): (1) cGS without treatment, (2) cGS plus MMF (20 mg/kg body weight in the food), (3) cGS plus a high dose of enalapril (12 mg/kg body weight in the drinking water), and (4) cGS plus MMF and enalapril in doses similar to group 2 and 3, respectively. After 15 weeks, systolic blood pressure, proteinuria, kidney function, glomerular and cortical matrix accumulation and expression of transforming growth factor(TGF)-beta1 and fibronectin as well as tissue infiltration with lymphocytes and macrophages were analyzed. Results: In comparison to the untreated cGS group, signs of renal disease were all significantly limited by MMF, enalapril and combined therapy. However, the relative reductions achieved were very similar in the three treatment groups. This was found on the basis of proteinuria (cGS: 149±14 mg/d, MMF -68%, enalapril -70% both -51%, the following results are expressed in the same manner), blood pressure (145 ± 7mmHg, -19mmHg, -20mmHg, -21mmHg), tubulointerstitial matrix accumulation (matrix score: 2.5 ± 0.3, -65%, -57%, -54%), protein expression of TGF-beta1 (189 ± 31 pg/mL, -52%, -54%, -43%) and fibronectin (2,921 ± 605 ng/mL, -49%, -65%, -66%), plasma creatinine levels (1.2 ± 0.3 mg/dL, -56%, -58%, -59%), plasma urea levels (157 ± 53 mg/dL -63%, -56%, -55%) as well as tubulointerstitial infiltration with CD4-(112 ± 14 cells/section, -62%, -62%, -64%), CD8-(83 ± 11 cells/section, -54%, -65%, -53%) and ED1- positive cells (186 ± 24 cells/section, -60%, -72%, -59%) (all p < 0.05 vs. cGS, all p = NS between the three treatment groups). The effects on glomerular matrix protein expression and accumulation and cell infiltration showed a similar pattern, but were more moderate. Conclusions: The present study shows that (1) MMF is as effective as a high dose of enalapril on a number of key morphological, functional and molecular characteristics of progressive renal fibrosis and (2) the dual anti-inflammatory, anti-fibrotic approach does not produce additive renoprotective effects. Taken together, the results (suggest that MMF and enalapril interfere with similar, or at least very closely related pathways mediating progression of renal disease.
- Subjects
PROTEINS; KIDNEY diseases; CELLS; CHRONIC diseases; FIBROSIS; EXTRACELLULAR matrix proteins; BLOOD; BLOOD pressure
- Publication
Kidney & Blood Pressure Research, 2004, Vol 27, Issue 5/6, p293
- ISSN
1420-4096
- Publication type
Article