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: Weidong Wang, Renfei Luo, Yu Lin, Feifei Wang, Peili Zheng, Moshe Levi, Tianxin Yang, Chunling Li
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 308 Issue 8 Pg. F910-22 (Apr 15 2015) ISSN: 1522-1466 [Electronic] United States
• PMID: 25694485 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Angiotensin II Type 1 Receptor Blockers
• Angiotensin-Converting Enzyme Inhibitors
• Aqp2 protein, mouse
• Aqp2 protein, rat
• Aquaporin 2
• Carrier Proteins
• Fumarates
• Inflammasomes
• Inflammation Mediators
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Nlrp3 protein, rat
• RNA, Messenger
• Receptors, Cytoplasmic and Nuclear
• aliskiren
• Renin

Topics

• Amides (pharmacology)
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Aquaporin 2 (drug effects, genetics, metabolism)
• Carrier Proteins (metabolism)
• Cells, Cultured
• Cytoprotection
• Disease Models, Animal
• Fumarates (pharmacology)
• Inflammasomes (antagonists & inhibitors, metabolism)
• Inflammation Mediators (metabolism)
• Kidney (drug effects, metabolism)
• Kidney Diseases (etiology, genetics, metabolism, prevention & control)
• Male
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein
• RNA, Messenger (metabolism)
• Rats, Wistar
• Receptors, Cytoplasmic and Nuclear (metabolism)
• Renin (antagonists & inhibitors, metabolism)
• Renin-Angiotensin System (drug effects)
• Time Factors
• Up-Regulation
• Ureteral Obstruction (complications, drug therapy, genetics, metabolism)