Infiltration with lymphocytes is found in both immune and non-immune 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 5/6 nephrectomy. Two days after surgery, male Wistar rats were allocated to the following groups: Sham surgery, 5/6 nephrectomy (HN) and HN+FTY720 (0.3 mg/kg BW). Therapy was continued for 6 weeks. Treatment with FTY720 was found to selectively reduce blood lymphocyte counts by 83% (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%), while hypertensive systemic blood pressure remained unchanged (160±5 vs. 161±5 mmHg P=NS). 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 TGF- 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- overexpression, macrophage infiltration and renal cell proliferation. These results suggest that infiltrating lymphocytes play an active, pro-fibrotic role in the progression of hypertensive renal tissue injury.