title: Aliskiren increases aquaporin-2 expression and attenuates lithium-induced nephrogenic diabetes insipidus.
abstract: The direct renin inhibitor aliskiren has been shown to be retained and persist in medullary collecting ducts even after treatment is discontinued, suggesting a new mechanism of action for this drug. The purpose of the present study was to investigate whether aliskiren regulates renal aquaporin expression in the collecting ducts and improves urinary concentrating defect induced by lithium in mice. The mice were fed with either normal chow or LiCl diet (40 mmol·kg dry food-1·day-1for 4 days and 20 mmol·kg dry food-1·day-1for the last 3 days) for 7 days. Some mice were intraperitoneally injected with aliskiren (50 mg·kg body wt-1·day-1in saline). Aliskiren significantly increased protein abundance of aquaporin-2 (AQP2) in the kidney inner medulla in mice. In inner medulla collecting duct cell suspension, aliskiren markedly increased AQP2 and phosphorylated AQP2 at serine 256 (pS256-AQP2) protein abundance, which was significantly inhibited both by adenylyl cyclase inhibitor MDL-12330A and by PKA inhibitor H89, indicating an involvement of the cAMP-PKA signaling pathway in aliskiren-induced increased AQP2 expression. Aliskiren treatment improved urinary concentrating defect in lithium-treated mice and partially prevented the decrease of AQP2 and pS256-AQP2 protein abundance in the inner medulla of the kidney. In conclusion, the direct renin inhibitor aliskiren upregulates AQP2 protein expression in inner medullary collecting duct principal cells and prevents lithium-induced nephrogenic diabetes insipidus likely via cAMP-PKA pathways.
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Tiezheng
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Clinical Laboratory, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; and.
authors.forename: Pinning
authors.initials: P
authors.lastname: Feng
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Miaojuan
authors.initials: M
authors.lastname: Qiu
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Qiaojuan
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Suchun
authors.initials: S
authors.lastname: Li
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Peili
authors.initials: P
authors.lastname: Zheng
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yonglun
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Department of Medicine, Division of Hypertension and Renal Diseases, University of Colorado Denver, Aurora, Colorado.
authors.forename: Moshe
authors.initials: M
authors.lastname: Levi
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Chunling
authors.initials: C
authors.lastname: Li
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; wangwd6@mail.sysu.edu.cn.
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
mesh_terms: D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use*; D000804:Angiotensin II / Q000652:urine; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051399:Aquaporin 2 / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D005650:Fumarates / Q000494:pharmacology / Q000627:therapeutic use*; D007679:Kidney Medulla / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000378:metabolism; D008094:Lithium; D008297:Male; D008810:Mice, Inbred C57BL; D011141:Polyuria / Q000139:chemically induced / Q000188:drug therapy; D011956:Receptors, Cell Surface / Q000378:metabolism; D000093342:Prorenin Receptor
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D005650:Fumarates; D011956:Receptors, Cell Surface; D000804:Angiotensin II; C446481:aliskiren; D008094:Lithium; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000093342:Prorenin Receptor
keywords: aquaporin; cAMP; direct renin inhibitor; urinary concentration