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- Title
The Lymphocyte Inhibitor FTY720 Slows the Progressive Course of Experimental Anti-Thy1-Induced, Chronic Renal Fibrosis.
- Authors
Martini, S.; Wang, Y.; Shimizu, F.; Kawachi, H.; Krämer, S.; Neumayer, H. -H.; Peters, H.
- Abstract
Objective: Progression is a hallmark of chronic renal diseases and histologically characterized by fibrosis and inflammation of the tubulointerstitial compartment independent of the underlying disorder. To define the role of lymphocytes in this process, the novel lymphocytespecific inhibitor FTY720 was administered to rats with progressive renal fibrosis, i.e. anti-thy1-induced chronic glomerulosclerosis (cGS). In this model, the initial and short-term inflammatory glomerular injury progresses self-perpetuatedly over months towards tubulointerstitial fibrosis by not primarily immune-mediated mechanisms. Methods: cGS was induced by murine anti-thy1 antibody injection into uni-nephrectomized male Wistar rats. Treatment with FTY720 (0.3 mg/kg body weight/d) was started 7 days after disease induction. In week 20, the following parameters were determined: proteinuria, blood lymphocyte number, plasma markers of kidney function, both glomerular and tubulointerstitial histological matrix accumulation (matrix score 0-4) and protein expression of transforming growth factor (TGF)-beta1, fibronectin and plasminogen-activator-inhibitor(PAI)-1 as well as renal macrophage and lymphocyte infiltration. Results: Treatment with FTY720 markedly reduced blood lymphocyte counts (-90%, p < 0.001) and renal lymphocyte infiltration (-64%, p < 0.01). In comparison to the untreated cGS animals, the lymphocyte reduction achieved significantly limited disease progression in this model, as shown by lowered proteinuria (73 ± 19 vs 171 ± 35 mg/d, p < 0.05), tubulointerstitial matrix expansion (matrix score 0.6 ± 0.2 vs 1.9 ± 0.5, p < 0.05) and TGF-beta1 (136 ± 7 vs 187 ± 16 pg/mL, p < 0.05), fibronectin (1,139 ± 145 vs 1,837 ± 228 ng/mL, p < 0.05) and PAI-1 expression (54 ± 8 vs 64 ± 6 ng/mL), as well as by improved renal function (plasma creatinine 0.64 ± 0.01 vs 0.75 ± 0.05 mg/dL, plasma urea 51 ± 4 vs 73 ± 11 mg/dL, both p < 0.05). Glomerular matrix protein expression and accumulation was moderately reduced by FTY720. Glomerular macrophage infiltration was not, tubulointerstitial macrophage infiltration was moderately, but not significantly decreased by FTY720 treatment. Conclusions: Lymphocyte inhibition by FTY720 limits disease progression towards tubulointerstitial fibrosis and renal insufficiency in experimental anti-thy1-induced, chronic glomerulosclerosis, although this process is not primarily immune-mediated. The data suggest that lymphocytes actively participate in the progression of chronic kidney diseases, and that FTY720 may be a novel approach to slow the progressive course of human chronic renal diseases.
- Subjects
KIDNEY diseases; FIBROSIS; INFLAMMATION; LYMPHOCYTES; IMMUNOGLOBULINS
- Publication
Kidney & Blood Pressure Research, 2004, Vol 27, Issue 5/6, p301
- ISSN
1420-4096
- Publication type
Article