RT Journal Article SR Electronic T1 NLRP3 Inflammasome Knockout Mice Are Protected against Ischemic but Not Cisplatin-Induced Acute Kidney Injury JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 465 OP 472 DO 10.1124/jpet.113.205732 VO 346 IS 3 A1 Hyun-Jung Kim A1 Dong Won Lee A1 Kameswaran Ravichandran A1 Daniel O. Keys A1 Ali Akcay A1 Quocan Nguyen A1 Zhibin He A1 Alkesh Jani A1 Danica Ljubanovic A1 Charles L. Edelstein YR 2013 UL http://jpet.aspetjournals.org/content/346/3/465.abstract AB We have demonstrated that caspase-1 is a mediator of both cisplatin-induced acute kidney injury (AKI) and ischemic AKI. As caspase-1 is activated in the inflammasome, we investigated the inflammasome in cisplatin-induced and ischemic AKI. Mice were injected with cisplatin or subjected to bilateral renal pedicle clamping. Immunoblot analysis of whole kidney after cisplatin-induced AKI revealed: 1) an increase in apoptosis-associated Speck-like protein containing a caspase recruitment domain (ASC), the major protein that complexes with nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing proteins (NLRP) 1 or 3 to form the inflammasome; 2) an increase in caspase-1 activity, caspase-5, and NLRP1, components of the NLRP1 inflammasome; and 3) a trend toward increased NLRP3. To determine whether the NLRP3 inflammasome plays an injurious role in cisplatin-induced AKI, we studied NLRP knockout (NLRP3−/−) mice. In cisplatin-induced AKI, the blood urea nitrogen, serum creatinine, acute tubular necrosis score, and tubular apoptosis score were not significantly decreased in NALP3−/− mice compared with wild-type mice. We have previously demonstrated the injurious role of caspase-1 in ischemic AKI. NLRP3, but not ASC or NLRP1, is increased in ischemic AKI. NLRP3−/− mice with ischemic AKI had significantly lower blood urea nitrogen, serum creatinine, and acute tubular necrosis and apoptosis scores than the wild-type controls. The difference in protection against cisplatin-induced AKI compared with ischemic AKI in NLRP3−/− mice was not explained by the differences in proinflammatory cytokines interleukin (IL)-1β, IL-6, chemokine (C-X-C motif) ligand 1, or tumor necrosis factor α. NLRP3 inflammasome is a mediator of ischemic AKI but not cisplatin-induced AKI, and further investigation of the NLRP1 inflammasome in cisplatin-induced AKI should prove interesting.