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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

NLRP3 Inflammasome Knockout Mice Are Protected against Ischemic but Not Cisplatin-Induced Acute Kidney Injury

Hyun-Jung Kim, Dong Won Lee, Kameswaran Ravichandran, Daniel O. Keys, Ali Akcay, Quocan Nguyen, Zhibin He, Alkesh Jani, Danica Ljubanovic and Charles L. Edelstein
Journal of Pharmacology and Experimental Therapeutics September 2013, 346 (3) 465-472; DOI: https://doi.org/10.1124/jpet.113.205732
Hyun-Jung Kim
Department of Pathology, University Hospital Dubrava, Zagreb, Croatia (D.L.); and Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado (H.-J.K., D.W.L., K.R., D.O.K., A.A., Q.N., Z.H., A.J., C.L.E.)
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Dong Won Lee
Department of Pathology, University Hospital Dubrava, Zagreb, Croatia (D.L.); and Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado (H.-J.K., D.W.L., K.R., D.O.K., A.A., Q.N., Z.H., A.J., C.L.E.)
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Kameswaran Ravichandran
Department of Pathology, University Hospital Dubrava, Zagreb, Croatia (D.L.); and Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado (H.-J.K., D.W.L., K.R., D.O.K., A.A., Q.N., Z.H., A.J., C.L.E.)
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Daniel O. Keys
Department of Pathology, University Hospital Dubrava, Zagreb, Croatia (D.L.); and Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado (H.-J.K., D.W.L., K.R., D.O.K., A.A., Q.N., Z.H., A.J., C.L.E.)
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Ali Akcay
Department of Pathology, University Hospital Dubrava, Zagreb, Croatia (D.L.); and Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado (H.-J.K., D.W.L., K.R., D.O.K., A.A., Q.N., Z.H., A.J., C.L.E.)
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Quocan Nguyen
Department of Pathology, University Hospital Dubrava, Zagreb, Croatia (D.L.); and Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado (H.-J.K., D.W.L., K.R., D.O.K., A.A., Q.N., Z.H., A.J., C.L.E.)
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Zhibin He
Department of Pathology, University Hospital Dubrava, Zagreb, Croatia (D.L.); and Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado (H.-J.K., D.W.L., K.R., D.O.K., A.A., Q.N., Z.H., A.J., C.L.E.)
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Alkesh Jani
Department of Pathology, University Hospital Dubrava, Zagreb, Croatia (D.L.); and Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado (H.-J.K., D.W.L., K.R., D.O.K., A.A., Q.N., Z.H., A.J., C.L.E.)
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Danica Ljubanovic
Department of Pathology, University Hospital Dubrava, Zagreb, Croatia (D.L.); and Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado (H.-J.K., D.W.L., K.R., D.O.K., A.A., Q.N., Z.H., A.J., C.L.E.)
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Charles L. Edelstein
Department of Pathology, University Hospital Dubrava, Zagreb, Croatia (D.L.); and Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado (H.-J.K., D.W.L., K.R., D.O.K., A.A., Q.N., Z.H., A.J., C.L.E.)
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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.

Footnotes

    • Received April 18, 2013.
    • Accepted July 3, 2013.
  • H.-J.K., D.W.L., and K.R. contributed equally to this work.

  • This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants R01 DK056851, R01 DK056851S1, K08 DK069512]; and grants from Fatih University School of Medicine, Department of Nephrology, Ankara, Turkey (to A.A.); Pusan National University School of Medicine, Pusan, South Korea (to D.W.L.); and Gyeongsang National University School of Medicine, Gyeongsangnam-do, South Korea (to H.-J.K.).

  • dx.doi.org/10.1124/jpet.113.205732.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 346 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 346, Issue 3
1 Sep 2013
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Inflammasome in AKI

Hyun-Jung Kim, Dong Won Lee, Kameswaran Ravichandran, Daniel O. Keys, Ali Akcay, Quocan Nguyen, Zhibin He, Alkesh Jani, Danica Ljubanovic and Charles L. Edelstein
Journal of Pharmacology and Experimental Therapeutics September 1, 2013, 346 (3) 465-472; DOI: https://doi.org/10.1124/jpet.113.205732

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Inflammasome in AKI

Hyun-Jung Kim, Dong Won Lee, Kameswaran Ravichandran, Daniel O. Keys, Ali Akcay, Quocan Nguyen, Zhibin He, Alkesh Jani, Danica Ljubanovic and Charles L. Edelstein
Journal of Pharmacology and Experimental Therapeutics September 1, 2013, 346 (3) 465-472; DOI: https://doi.org/10.1124/jpet.113.205732
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