Our long-term goal is to prevent/treat acute kidney injury. We are using cisplatin toxicity as a model of renal injury, in vitro using cultured mouse kidney proximal tubule cells, and in vivo using wild-type and transgenic mice. We have established that inhibition of a cell cycle-associated enzyme, cyclin-dependent kinase-2 (Cdk2), protect from cytotoxicity in vitro and protects from kidney injury in vivo caused by cisplatin administration. Based on these findings, we developed two transgenic mouse strains resistant to cisplatin-induced acute renal injury because of specific cdk2 inhibition. We found that several pathways of cell death were dependent on Cdk2 activity and contribute to cisplatin cytotoxicity. We hypothesize that cell death activated by cisplatin and dependent on Cdk2 kinase activity can likely be explained by intersecting rather than parallel pathways. Now we find that in response to cisplatin, Cdk2 phosphorylates two proteins, p21 and Bcl xL, that directly and indirectly could have effects on cell death pathways. In our first specific aim we will investigate whether these proteins provide the intersections of cell cycle and cell death. We hypothesize that Cdk2 inhibition would be an effective short- and long-term strategy to prevent AKI. Our recently developed transgenic mice in which induced expression of either p21 or DN-Cdk2 protected from cisplatin nephrotoxicity confirmed the first half of this hypothesis. The second half of our hypothesis will be addressed in this second specific aim, which will determine whether Cdk2inhibition merely delays nephrotoxicity and whether Cdk2 inhibition and cisplatin exposure causes longer-term effects on kidney recovery.

Public Health Relevance

Acute kidney injury (AKI) is a common disorder affecting up to 5% of hospitalized patients. Despite our increased understanding of the incidence and consequences of AKI, morbidity and mortality associated with this syndrome in critically ill patients has remained above 50%. AKI is an independent risk factor in the setting of multi organ failure leading to death and disability. The financial costs of AKI are estimated to be 8 billion dollars per year, or about $130,000 per life-year saved. It is unlikely that this high mortality and associated cost will be reduced until we understand the cellular and molecular mechanisms of cell injury and recovery. We found that cell cycle enzyme inhibitors will totally protect kidney cells in vitro from cisplatin cytotoxicity and significantly diminish morphologic and functional AKI in vivo. We have developed transgenic mice that are resistant to AKI. The mechanism of protection and its use in vivo will be investigated. Our proposal will lead to the development of agents that can be used to prevent AKI, which will directly impact patient care and well-being.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054471-13
Application #
8337721
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
1998-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
13
Fiscal Year
2012
Total Cost
$267,982
Indirect Cost
$72,232
Name
Biomedical Research Fdn/Central Arkansas
Department
Type
DUNS #
876538836
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Hodeify, Rawad; Megyesi, Judit; Tarcsafalvi, Adel et al. (2013) Gender differences control the susceptibility to ER stress-induced acute kidney injury. Am J Physiol Renal Physiol 304:F875-82
Hodeify, Rawad; Tarcsafalvi, Adel; Megyesi, Judit et al. (2011) Cdk2-dependent phosphorylation of p21 regulates the role of Cdk2 in cisplatin cytotoxicity. Am J Physiol Renal Physiol 300:F1171-9
Price, Peter M (2010) A role for novel cell-cycle proteins in podocyte biology. Kidney Int 77:660-1
Hodeify, Rawad; Megyesi, Judit; Tarcsafalvi, Adel et al. (2010) Protection of cisplatin cytotoxicity by an inactive cyclin-dependent kinase. Am J Physiol Renal Physiol 299:F112-20
Price, Peter M; Safirstein, Robert L; Megyesi, Judit (2009) The cell cycle and acute kidney injury. Kidney Int 76:604-13
Yu, Fang; Megyesi, Judit; Price, Peter M (2008) Cytoplasmic initiation of cisplatin cytotoxicity. Am J Physiol Renal Physiol 295:F44-52
Wei, Qingqing; Dong, Guie; Yang, Tianxin et al. (2007) Activation and involvement of p53 in cisplatin-induced nephrotoxicity. Am J Physiol Renal Physiol 293:F1282-91
Yu, Fang; Megyesi, Judit; Safirstein, Robert L et al. (2007) Involvement of the CDK2-E2F1 pathway in cisplatin cytotoxicity in vitro and in vivo. Am J Physiol Renal Physiol 293:F52-9
Price, Peter M; Yu, Fang; Kaldis, Philipp et al. (2006) Dependence of cisplatin-induced cell death in vitro and in vivo on cyclin-dependent kinase 2. J Am Soc Nephrol 17:2434-42
Yu, Fang; Megyesi, Judit; Safirstein, Robert L et al. (2005) Identification of the functional domain of p21(WAF1/CIP1) that protects cells from cisplatin cytotoxicity. Am J Physiol Renal Physiol 289:F514-20

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