The challenge area (03-DK-102) is the development and validation of novel, noninvasive methods to detect and monitor disorders of relevance to NIDDK at early stages of disease before major organ damage and dysfunction has occurred. Novel diagnostic methodologies relevant to disorders that are currently difficult to detect early in the course of disease and/or that require invasive procedures (such as tissue or organ biopsies) are of highest priority. The specific challenge topic is the development of early, sensitive, non-invasive methods to diagnose acute kidney injury. We propose to examine utility of renalase, a novel molecule discovered in our laboratory, as an early and sensitive biomarker for acute kidney injury. Acute kidney injury (AKI) is a clinical condition commonly associated with sepsis, surgery, and certain drugs, and which affects up to 20% of hospitalized patients. Epidemiologic data indicate those who develop AKI are more likely to die than those who don't, and the risk is proportional to the severity of the renal injury and of the concomitant reduction in renal function. The development of effective treatment protocols for AKI has been hampered by the fact the diagnosis relies heavily of serum creatinine measurements, and is, therefore, often made 48-72 hours following the original insult. There is a clear and pressing need to identify patients with AKI early, and the best approach is believed to involve the identification biomarkers and their validation in human clinical trials. Renalase is an amine oxidase that metabolizes catecholamines such as dopamine, epinephrine and norepinephrine. It is synthesized by the renal proximal tubule, secreted in blood and continuously excreted in urine in the basal state. Renalase levels can be measured either by Western blot or ELISA. Preliminary data suggest that renalase is a novel biomarker for AKI. Moderately severe ischemic insults (global ischemia for 45 min), caused a dramatic and long-lasting decrease in urinary renalase excretion. These data are very exciting and suggest that urinary renalase may be an early biomarker for ischemic AKI. The main goal of this proposal is test the hypothesis that urinary renalase can serve as an early and sensitive biomarker for AKI in rodents, and that renalase administration is a useful therapeutic option to treat AKI in rodents. If the proposed studies are successful, future studies (not part of this proposal) will aim to validate renalase as a biomarker of AKI in humans using the TRIBE-AKI database and or similar available databases, and to test the therapeutic utility of recombinant renalase in AKI in humans.

Public Health Relevance

Acute kidney injury (AKI), a clinical condition commonly associated with sepsis, surgery, and certain drugs, affects up to 20% of hospitalized patients and is associated with increased mortality. The development of effective treatment protocols for AKI has been hampered by the fact the diagnosis relies heavily of serum creatinine measurements, and is, therefore, often made 48-72 hours following the original insult. There is a clear and pressing need to identify patients with AKI early, and the best approach is believed to involve the identification biomarkers and their validation in human clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
1RC1DK086465-01
Application #
7820609
Study Section
Special Emphasis Panel (ZRG1-DKUS-A (58))
Program Officer
Ketchum, Christian J
Project Start
2010-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
1
Fiscal Year
2010
Total Cost
$500,000
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kolodecik, Thomas R; Reed, Anamika M; Date, Kimie et al. (2017) The serum protein renalase reduces injury in experimental pancreatitis. J Biol Chem 292:21047-21059
Guo, Xiaojia; Hollander, Lindsay; MacPherson, Douglas et al. (2016) Inhibition of renalase expression and signaling has antitumor activity in pancreatic cancer. Sci Rep 6:22996
Hollander, Lindsay; Guo, Xiaojia; Velazquez, Heino et al. (2016) Renalase Expression by Melanoma and Tumor-Associated Macrophages Promotes Tumor Growth through a STAT3-Mediated Mechanism. Cancer Res 76:3884-94
Quelhas-Santos, Janete; SerrĂ£o, Maria Paula; Soares-Silva, Isabel et al. (2015) Renalase regulates peripheral and central dopaminergic activities. Am J Physiol Renal Physiol 308:F84-91
Qi, Chaojun; Wang, Ling; Zhang, Minfang et al. (2015) Serum Renalase Levels Correlate with Disease Activity in Lupus Nephritis. PLoS One 10:e0139627
Wang, Ling; Velazquez, Heino; Chang, John et al. (2015) Identification of a receptor for extracellular renalase. PLoS One 10:e0122932
Wang, Ling; Velazquez, Heino; Moeckel, Gilbert et al. (2014) Renalase prevents AKI independent of amine oxidase activity. J Am Soc Nephrol 25:1226-35
Guo, Xiaojia; Wang, Ling; Velazquez, Heino et al. (2014) Renalase: its role as a cytokine, and an update on its association with type 1 diabetes and ischemic stroke. Curr Opin Nephrol Hypertens 23:513-8
Lee, H Thomas; Kim, Joo Yun; Kim, Mihwa et al. (2013) Renalase protects against ischemic AKI. J Am Soc Nephrol 24:445-55
Sizova, Daria; Velazquez, Heino; Sampaio-Maia, Benedita et al. (2013) Renalase regulates renal dopamine and phosphate metabolism. Am J Physiol Renal Physiol 305:F839-44

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