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: Hyun-Jung Kim, Dong Won Lee, Kameswaran Ravichandran, Daniel O Keys, Ali Akcay, Quocan Nguyen, Zhibin He, Alkesh Jani, Danica Ljubanovic, Charles L Edelstein
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 346 Issue 3 Pg. 465-72 (Sep 2013) ISSN: 1521-0103 [Electronic] United States
• PMID: 23833276 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Carrier Proteins
• Interleukin-1alpha
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Caspases
• Caspase 1
• Cisplatin

Topics

• Acute Kidney Injury (chemically induced, genetics, prevention & control)
• Animals
• Antineoplastic Agents
• Carrier Proteins (genetics, physiology)
• Caspase 1 (metabolism)
• Caspases (metabolism)
• Cell Line, Tumor
• Cisplatin
• Enzyme-Linked Immunosorbent Assay
• Interleukin-1alpha (metabolism)
• Interleukin-1beta (metabolism)
• Ischemia (complications)
• Kidney (pathology)
• Kidney Tubules, Proximal (pathology)
• Macrophages (drug effects, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein
• Neutrophil Infiltration (genetics, physiology)
• Renal Circulation (physiology)