Cisplatin and other platinum derivatives are important chemotherapeutic agents used to treat solid tumors. A known complication of cisplatin administration is acute kidney injury (AKI) which often necessitates dose reduction or withdrawal. Therefore, an understanding of the pathogenesis of cisplatin-induced AKI is important for the development of adjunctive therapies to prevent AKI and to lessen the need for dose decrease or drug withdrawal. IL-33 is a newly described pro-inflammatory cytokine in the IL-1 family that signals via the ST2 receptor. Our published data demonstrate that IL-33 inhibition attenuates CD4 T cell infiltration, renal failure and ATN, that administration of recombinant IL-33 worsens cisplatin-induced AKI and increases the chemokine CXCL1 in wild type but not CD4 -/- mice and that CD4 T cell-depletion is protective. The overall hypothesis presented in this grant provides an integrated pathophysiological schema whereby IL-33 results in CD4 T cell recruitment in the kidney, release of CXCL1 from CD4 T cells and cisplatin-induced AKI. Complementary studies will be performed in mice with cisplatin-induced AKI, mouse cancer models, endothelial cells and freshly isolated proximal tubules.
Specific Aim 1 focuses on the cellular source of IL-33 and ST2 in the kidney.
In Specific Aim 2, we shall determine the injurious role of IL-33 in cisplatin-induced AKI. Complimentary novel pharmacological and genetic techniques of IL-33 or ST2 inhibition will be used. The effect of IL-33, ST2 and CXCL1 inhibition and CD4 T cell knockout on cisplatin-induced AKI and the chemotherapeutic efficacy of cisplatin in mouse cancer models will be studied.
Specific Aim 3 focuses on the IL-33-dependent production of CXCL1 by CD4 T cells in the kidney. The effect of CXCL1 inhibitors on AKI will be determined. CXCL1 can directly cause cell death in vitro. The effect of CXCL1 to directly cause proximal tubule injury in vitro in the absence of inflammation, will be determined. Novel experiments investigating the effect on protection against cisplatin-induced AKI by CD4 T cell depletion followed by adoptive transfer of CD4 T cells with or without the molecule of interest e.g. IL-33 will be performed. The relevance of these studies to clinical cisplatin-induced AKI is substantial and the discovery of novel mediators of cisplatin-induced AKI should provide clues to future therapies. This is particularly true because of the current availability of anti-inflammatory agents that are FDA- approved, IL-33/ST2 inhibitors that are entering clinical studies and CXCL1 inhibitors that are in clinical studies.

Public Health Relevance

Cisplatin is the most commonly used anti-cancer drug for the treatment of solid tumors. Acute kidney injury is cisplatin's major dose-limiting side effect. Cancer is a common cause of death in the Veteran population. In addition, the risk factors for acute kidney injury are higher in the Veteran population due to the presence of cardiovascular disease, diabetes mellitus, cancer and chronic kidney disease. The grant proposal studies the pathophysiology of cisplatin-induced acute kidney injury, especially as it relates to inflammation, and tests novel therapeutic agents i mice with or without cancer. A better understanding of the pathophysiology of cisplatin-induced acute kidney injury may result in therapeutic agents that ameliorate the kidney injury and improve the survival of cancer patients.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX001737-01A1
Application #
8440535
Study Section
Nephrology (NEPH)
Project Start
2013-01-01
Project End
2016-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
Total Cost
Indirect Cost
Name
VA Eastern Colorado Health Care System
Department
Type
DUNS #
003252830
City
Denver
State
CO
Country
United States
Zip Code
80220
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Jain, Swati; Keys, Daniel; Ljubanovic, Danica et al. (2015) Protection Against Cold Storage-Induced Renal Tubular Cell Apoptosis. Transplantation 99:2311-6
Jain, Swati; Keys, Daniel; Nydam, Trevor et al. (2015) Inhibition of autophagy increases apoptosis during re-warming after cold storage in renal tubular epithelial cells. Transpl Int 28:214-23
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Kim, Hyun-Jung; Lee, Dong Won; Ravichandran, Kameswaran et al. (2013) NLRP3 inflammasome knockout mice are protected against ischemic but not cisplatin-induced acute kidney injury. J Pharmacol Exp Ther 346:465-72
Akcay, Ali; Nguyen, Quocan; He, Zhibin et al. (2011) IL-33 exacerbates acute kidney injury. J Am Soc Nephrol 22:2057-67