Biologic Effects of Cdk2 Substrate Phosphorylation on Acute Kidney Injury

Summary

Principal Investigator: Peter M Price
Abstract: DESCRIPTION (provided by applicant): Ourlong-termgoalistoprevent/treatacutekidneyinjury. Weareusingcisplatintoxicityasamodelofrenal 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-dependentkinase-2 (Cdk2), protects 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. Wefoundthatinresponsetocisplatin,Cdk2phosphorylatestwoproteins,p21andBcl-xL,thatdirectly and indirectly could have effects on cell death pathways. In our first specific aim we will investigate whether these phosphorylations have biologic effects on the proteins, and the mechanism of these effects. We hypothesized that Cdk2 inhibition is an effective strategy to prevent AKI. Our recently developed transgenic mice in which Cdk2 inhibitors can be induced in kidney tubules confirmed this hypothesis for cisplatin nephrotoxicity. In our second specific aim our transgenic mice will be used to determine whether Cdk2 inhibition will ameliorate other models of AKI, such as ischemia-reperfusion, nephrotoxic injury, or ER stress. We will determine whether the protein phosphorylations described above also occur in vivo, and using our transgenic mice, whether they correlate to the activation of kidney cell death pathways. PUBLIC HEALTH RELEVANCE: Acute kidney injury (AKI) is a common disorder affecting up to 5% of hospitalized patients. The overall mortality following AKI has remained at approximately 50% since the mid-1960's. 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 and which is highly relevant to veterans'health issues and to the VA mission.
Funding Period: 2011-01-01 - 2014-12-31
more information: NIH RePORT

Research Grants

Detail Information

Research Grants30

  1. Role of Meprin A in Acute Kidney Injury
    GUR PRASAD KAUSHAL; Fiscal Year: 2013
    ..In addition the study will identify meprin A-mediated urinary markers for early detection of AKI. Therefore, the proposal is clinically relevant to the VA patient population since a large segment of veterans suffer from AKI. ..
  2. Novel endonuclease-targeted approaches to nephroprotection
    Alexei G Basnakian; Fiscal Year: 2013
    ..This proposal will likely result in new therapies, and may eventually allow saving human lives, improving the health of veterans, and decreasing the number of disabilities in the veteran population. ..
  3. 5-HT Stimulation of Mitochondrial Biogenesis and Acute Kidney Injury
    Rick G Schnellmann; Fiscal Year: 2013
    ..Ultimately, these studies may lead to new therapeutic approaches to increase cell and organ survival and function in numerous pathologic conditions. ..
  4. Acute Renal Failure: Mechanisms and Adaptive Responses
    Richard A Zager; Fiscal Year: 2013
    ..By so doing, new insights into ischemia- induced tissue modifications, with implications for subsequent tissue injury, will result. ..