title: NLRP3 inflammasome knockout mice are protected against ischemic but not cisplatin-induced acute kidney injury.
abstract: 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.
authors.affiliation: Department of Pathology, University Hospital Dubrava, Zagreb, Croatia.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Dong Won
authors.initials: DW
authors.lastname: Lee
authors.forename: Kameswaran
authors.initials: K
authors.lastname: Ravichandran
authors.forename: Daniel
authors.initials: D
authors.lastname: O Keys
authors.forename: Ali
authors.initials: A
authors.lastname: Akcay
authors.forename: Quocan
authors.initials: Q
authors.lastname: Nguyen
authors.forename: Zhibin
authors.initials: Z
authors.lastname: He
authors.forename: Alkesh
authors.initials: A
authors.lastname: Jani
authors.forename: Danica
authors.initials: D
authors.lastname: Ljubanovic
authors.forename: Charles L
authors.initials: CL
authors.lastname: Edelstein
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics* / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D020170:Caspase 1 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin; D004797:Enzyme-Linked Immunosorbent Assay; D053582:Interleukin-1alpha / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007511:Ischemia / Q000150:complications*; D007668:Kidney / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020556:Neutrophil Infiltration / Q000235:genetics / Q000502:physiology; D012079:Renal Circulation / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D020169:Caspases; D020170:Caspase 1; D002945:Cisplatin