title: Aliskiren restores renal AQP2 expression during unilateral ureteral obstruction by inhibiting the inflammasome.
abstract: Ureteral obstruction is associated with reduced expression of renal aquaporins (AQPs), urinary concentrating defects, and an enhanced inflammatory response, in which the renin-angiotensin system (RAS) may play an important role. We evaluated whether RAS blockade by a direct renin inhibitor, aliskiren, would prevent the decreased renal protein expression of AQPs in a unilateral ureteral obstruction (UUO) model and what potential mechanisms may be involved. UUO was performed for 3 days (3UUO) and 7 days (7UUO) in C57BL/6 mice with or without aliskiren injection. In 3UUO and 7UUO mice, aliskiren abolished the reduction of AQP2 protein expression but not AQP1, AQP3, and AQP4. mRNA levels of renal AQP2 and vasopressin type 2 receptor were decreased in obstructed kidneys of 7UUO mice, which were prevented by aliskiren treatment. Aliskiren treatment was also associated with a reduced inflammatory response in obstructed kidneys of UUO mice. Aliskiren significantly decreased mRNA levels of several proinflammatory factors, such as transforming growth factor-β and tumor necrosis factor-α, seen in obstructed kidneys of UUO mice. Interestingly, mRNA and protein levels of the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome components apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, and IL-1β were dramatically increased in obstructed kidneys of 7UUO mice, which were significantly suppressed by aliskiren. In primary cultured inner medullary collecting duct cells, IL-1β significantly decreased AQP2 expression. In conclusions, RAS blockade with the direct renin inhibitor aliskiren increased water channel AQP2 expression in obstructed kidneys of UUO mice, at least partially by preventing NLRP3 inflammasome activation in association with ureteral obstruction.
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;
authors.forename: Renfei
authors.initials: R
authors.lastname: Luo
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: Feifei
authors.initials: F
authors.lastname: Wang
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: Division of Renal Diseases and Hypertension, Anschutz Medical Campus, University of Colorado, Aurora, Colorado; and.
authors.forename: Moshe
authors.initials: M
authors.lastname: Levi
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Department of Medicine, University of Utah, and Veterans Affairs Medical Center, Salt Lake City, Utah.
authors.forename: Tianxin
authors.initials: T
authors.lastname: Yang
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; lichl3@mail.sysu.edu.cn.
authors.forename: Chunling
authors.initials: C
authors.lastname: Li
mesh_terms: D000577:Amides / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D051399:Aquaporin 2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D019610:Cytoprotection; D004195:Disease Models, Animal; D005650:Fumarates / Q000494:pharmacology*; D058847:Inflammasomes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D051399:Aquaporin 2; D002352:Carrier Proteins; D005650:Fumarates; D058847:Inflammasomes; D018836:Inflammation Mediators; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D012083:Renin; D000092502:Renin Inhibitors; C496024:Aqp2 protein, mouse; C496025:Aqp2 protein, rat; C492716:Nlrp3 protein, mouse; C573346:Nlrp3 protein, rat; C446481:aliskiren
keywords: aquaporin 2; obstructive nephropathy; renin inhibition; water channel