AIM: The direct renin inhibitor aliskiren displays antihypertensive and antialbuminuric effects in humans and in animal models.Emerging evidence has shown that aliskiren localizes and persists in medullary collecting ducts even after treatment was discontinued.The purpose of the present study was to investigate whether aliskiren regulates renal aquaporin expression and improves urinary concentrating defect induced by lithium. METHODS: The mice were either fed with normal chow or Li Cl diet(40 mmol / kg dry food per day for first 4 days and 20 mmol / kg dry food per day for last 3 days) for seven days. Some mice were intraperitoneally injected aliskiren(50 mg/kg BW per day in saline). RESULTS: Mice injected aliskiren developed decreased urine output and increased urine osmolality when compared with controls. Aliskiren significantly increased protein abundance of AQP2 and phosphorylated-S256 AQP2 in the kidney inner medulla. Immunohistochemistry and immunofluoresence showed increased apical and intracellular labeling of AQP2 and p S256-AQP2 in collecting duct principal cells of kidneys in mice treated with aliskiren. Aliskiren treatment prevented urinary concentrating defect in lithium-treated mice,and improved the downregulation of AQP2 and p S256-AQP2 protein abundance in inner medulla of the kidney. In primary cultured rat inner medulla collecting duct cells,aliskiren dramatically increased AQP2 protein abundance which was significantly inhibited either by PKA inhibitor H89 or by adenylyl cyclase inhibitor MDL12330,indicating an involvement of the c AMP signalling pathway in mediating aliskiren-induced increased AQP2 expression. CONCLUSION: The direct renin inhibitor aliskiren upregulates AQP2 protein expression in inner medullary collecting duct principal cells and prevents lithium-induced nephrogenic diabetes insipidus( NDI) likely via PKA-c AMP pathways. AIM: The direct renin inhibitor aliskiren displays antihypertensive and antialbuminuric effects in humans and in animal models. Emerging evidence has shown that aliskiren localizes and persists in medullary collecting ducts even after treatment was discontinued. The purpose of the present study was to investigate whether aliskiren regulates METHODS: The mice were fed either normal chow or LiCl diet (40 mmol / kg dry food per day for first 4 days and 20 mmol / kg dry food per day for last 3 days) for seven days. Some mice were intraperitoneally injected aliskiren (50 mg / kg BW per day in saline). RESULTS: Mice injected aliskiren developed decreased urine output and increased urine osmolality when compared with controls. Aliskiren significantly increased protein abundance of AQP2 and phosphorylated-S256 AQP2 in the kidney inner medulla. Immunohistochemistry and immunofluoresence showed increased api cal and intracellular labeling of AQP2 and p S256-AQP2 in collecting duct principal cells of kidneys in mice treated with aliskiren. Aliskiren treatment prevented urinary concentrating defect in lithium-treated mice, and improved the downregulation of AQP2 and p S256-AQP2 protein abundance in inner medulla of the kidney. In primary cultured rat inner medulla collecting duct cells, aliskiren very increased AQP2 protein abundance which was significantly inhibited either by PKA inhibitor H89 or by adenylyl cyclase inhibitor MDL 12330, indicating an involvement of the c AMP signaling pathway in mediating aliskiren -induced increased AQP2 expression. CONCLUSION: The direct renin inhibitor aliskiren upregulates AQP2 protein expression in inner medullary collecting duct principal cells and prevents lithium-induced nephrogenic diabetes insipidus (NDI) likely via PKA-c AMP pathways.