The aims of this study were to 1) determine whether renal localization of aliskiren and its anti-hypertensive and renoprotective effects persist after stopping administration of the drug, and 2) define the renal localization of aliskiren by light microscopy autoradiography. Hypertensive double transgenic rats (dTGR) overexpressing genes for human renin and angiotensinogen were treated with aliskiren (3 mg/kg/day sc; osmotic minipumps) or enalapril (18mg/L in drinking water). After 2 weeks treatment dTGR were assigned to either continued treatment with aliskiren ("continued"), or to cessation of their respective treatment ("stopped") for three weeks washout. One week treatment with aliskiren and enalapril reduced BP and albuminuria vs baseline. After cessation of either treatment, blood pressure had returned to pre-treatment levels and albuminuria remained relatively low for 1 week, but rose thereafter similarly in both groups. In contrast, renal mRNA for TGF-β and renal collagen IV was reduced by aliskiren (continued and stopped groups), but not after cessation of enalapril. Similar patterns were found for collagen IV protein expression. Even 3 weeks after stopping aliskiren treatment, renal levels of the drug exceeded its IC50, whereas enalaprilat was not detected. To localize aliskiren accumulation, Wistar rats were treated with [³H]-aliskiren for 7 days. Autoradiography demonstrated specific labeling in glomeruli, arterioles, and afferent arterioles as well as in the distal nephron. Labeling could still be observed even after 7 days washout. These results suggest that the renophilic properties of aliskiren are different from enalapril and could have contributed to the renoprotective mechanism of this renin inhibitor.