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.