Selective lymphocyte inhibition by FTY720 slows the progressive course of chronic anti-thy 1 glomerulosclerosis.
BACKGROUND
Progression is a hallmark of chronic renal disease and histologically characterized by fibrosis and inflammation of the tubulointerstitial compartment. To define the role of lymphocytes in this process, the novel lymphocyte-specific inhibitor FTY720 was administered to rats with anti-thy 1-induced chronic progressive glomerulosclerosis. In this model, the initial and short-term inflammatory glomerular injury progresses self-perpetuatedly toward tubulointerstitial fibrosis by not primarily immune-mediated, intrarenal mechanisms.


METHODS
Chronic progressive glomerulosclerosis was induced by murine anti-thy 1 antibody injection into uninephrectomized rats. Treatment with FTY720 (0.3 mg/kg body weight) was started 7 days after disease induction. Proteinuria was measured every 4 weeks. In week 20, the following parameters were determined: blood lymphocyte number, kidney function, both glomerular and tubulointerstitial histologic matrix accumulation, protein expression of transforming growth factor-beta1 (TGF-beta1), fibronectin, and plasminogen activator inhibitor-1 (PAI-1) as well as infiltration with macrophages and lymphocytes.


RESULTS
Treatment with FTY720 lowered blood lymphocyte count and renal lymphocyte infiltration highly significantly. In comparison to the untreated chronic progressive glomerulosclerosis animals, the lymphocyte depletion achieved significantly limited the progression of the disease, as shown by lowered proteinuria, tubulointerstitial matrix expansion, and TGF-beta1, fibronectin, and PAI-1 expression, as well as improved renal function. Glomerular matrix protein expression and accumulation was moderately lowered by FTY720. Glomerular macrophage infiltration was not, tubulointerstitial macrophage infiltration was moderately, but not significantly, decreased by FTY720 treatment.


CONCLUSIONS
Lymphocyte depletion by FTY720 limits the progression of anti-thy 1-induced glomerulosclerosis toward chronic tubulointerstitial fibrosis and renal insufficiency. The data suggest that lymphocytes actively participate in the progression of chronic experimental kidney disease, and that FTY720 may be a novel approach to slow the progressive course of human chronic renal diseases.
Peters
Harm
H
Department of Nephrology and Center of Cardiovascular Research, Charité, University Medicine Berlin, Charité Campus Mitte, Humboldt University, Berlin, Germany. Harm.Peters@charite.de
Martini
Sebastian
S
Wang
Yingrui
Y
Shimizu
Fuijo
F
Kawachi
Hiroshi
H
Krämer
Stephanie
S
Neumayer
Hans-H
HH
D000818:Animals; D001794:Blood Pressure; D001806:Blood Urea Nitrogen; D001835:Body Weight; D003404:Creatinine / Q000097:blood; D005109:Extracellular Matrix / Q000187:drug effects / Q000473:pathology; D005355:Fibrosis; D000068876:Fingolimod Hydrochloride; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D006339:Heart Rate; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007518:Isoantibodies; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D011409:Propylene Glycols / Q000494:pharmacology*; D011507:Proteinuria / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013110:Sphingosine / Q000031:analogs & derivatives
D007166:Immunosuppressive Agents; D007518:Isoantibodies; D011409:Propylene Glycols; C035678:anti-Thy antibody; D003404:Creatinine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine