The lymphocyte migration inhibitor FTY720 attenuates experimental hypertensive nephropathy.
The lymphocyte migration inhibitor FTY720 attenuates experimental hypertensive nephropathy. Infiltration with lymphocytes is found in both immune and nonimmune chronic kidney diseases. In a rat model of immune-initiated progressive glomerulosclerosis, selective inhibition of lymphocyte infiltration by FTY720 showed significant beneficial effects on renal fibrosis. To test whether this translates into hypertensive nephropathy (HN), the lymphocyte migration inhibitor was administered to rats following nephrectomy. Two days after surgery, male Wistar rats were allocated to the following groups: Sham surgery, nephrectomy (HN), and HN + FTY720 (0.3 mg/kg body wt). Therapy was continued for 6 wk. Treatment with FTY720 was found to selectively reduce blood lymphocyte counts by 85% (P < 0.001 vs. HN) and renal lymphocyte infiltration (CD-3 positive cells) by 63% (P < 0.01 vs. HN) as was anticipated. Lymphocyte depletion went along with a significant reduction in proteinuria (-28%), whereas hypertensive systemic blood pressure remained unchanged (160 +/- 5 vs. 161 +/- 5 mmHg, P = not significant). The markedly increased histological tubulointerstitial and glomerular matrix protein accumulation, collagen, laminin, and fibronectin deposition were all significantly impeded in the FTY720-treated animals. The anti-fibrotic effects of FTY720 were paralleled by significant reductions in renal transforming growth factor (TGF)-beta overexpression, macrophage infiltration, and cell proliferation. In conclusion, the lymphocyte migration inhibitor FTY720 significantly limits histological and molecular fibrosis in a model of hypertensive nephropathy without affecting increased systemic blood pressure. Prevention of renal lymphocytes' infiltration by FTY720 was followed by significant reductions in TGF-beta overexpression, macrophage infiltration, and renal cell proliferation. These results suggest that infiltrating lymphocytes play an active, profibrotic role in the progression of hypertensive renal tissue injury.
Department of Nephrology and Center for Cardiovascular Research, Charité Universitätsmedizin Berlin, Charité Campus Mitte, Humboldt University Berlin, D-10117 Berlin, Germany.
Stephanie
S
Krämer
Eva
E
Binder
Tanja
T
Loof
Yingrui
Y
Wang-Rosenke
Sebastian
S
Martini
Dmytro
D
Khadzhynov
Klemens
K
Budde
Hans-H
HH
Neumayer
Harm
H
Peters
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D000068876:Fingolimod Hydrochloride; D006973:Hypertension / Q000150:complications / Q000188:drug therapy*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D009392:Nephrectomy; D011409:Propylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000378:metabolism
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D016212:Transforming Growth Factor beta; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine