Sepsis and septic shock in-hospital are associated with a high incidence of acute renal failure (ARF) estimated at 20 and 50%, respectively. Moreover, the combination of sepsis and ARF leads to a very high mortality ranging from 50-80%. Understanding the early vasoactive and the later proinflammatory events which cause ARF during endotoxemia would be a major medical advance, thereby allowing the development of pathogenetic-based interventions. This proposal focuses on early vasoactive endotoxemia-related events which cause systemic arterial vasodilation (e.g. nitric oxide, prostaglandins) and the compensatory vasoconstrictors (e.g. norepinephrine, angiotensin, endothelin, thromboxane) which support blood pressure but lead to renal vasoconstriction. This renal vasoconstriction renders the kidney more susceptible to the proinflammatory events of endotoxemia, such as generation of superoxide, peroxynitrite, and cytokines such as interleukin-18. In addition to selective renal denervation, there are now specific inhibitors to test the involvement of inducible nitric oxide synthase, prostaglandin and thromboxane in sepsis. Molecular biological techniques using knockout and transgemc mice will also be used to examine the role of various systemic and renal vasodilators and vasoconstrictors during endotoxemia. Understanding the role and interaction between these factors should allow the development of potential interventions in sepsis which could dramatically decrease the incidence of ARF, morbidity and mortality. The availability of potent scavengers of superoxide and antiserum to interleukin-18 also will allow not only the study of early vasoactive events but also the later pro-inflammatory events. Thus, the potential impact of the research on sepsis and sepsis-mediated ARF is substantial. The goal is to unravel the multifaceted events which occur during sepsis, including their interactions, so that effective interventions can be developed and tested in humans with sepsis. The ultimate goal therefore is to understand and prevent the ARF, morbidity and mortality associated with sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052599-07
Application #
6747649
Study Section
General Medicine B Study Section (GMB)
Program Officer
Wilder, Elizabeth L
Project Start
1998-01-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
7
Fiscal Year
2004
Total Cost
$292,612
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Wang, Wei; Zolty, Einath; Falk, Sandor et al. (2008) Endotoxemia-related acute kidney injury in transgenic mice with endothelial overexpression of GTP cyclohydrolase-1. Am J Physiol Renal Physiol 294:F571-6
Wang, Wei; Zolty, Einath; Falk, Sandor et al. (2006) Pentoxifylline protects against endotoxin-induced acute renal failure in mice. Am J Physiol Renal Physiol 291:F1090-5
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Poole, Brian; Wang, Wei; Chen, Yung-Chang et al. (2005) Role of heme oxygenase-1 in endotoxemic acute renal failure. Am J Physiol Renal Physiol 289:F1382-5
Tao, Yunxia; Kim, Jun; Faubel, Sarah et al. (2005) Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease. Proc Natl Acad Sci U S A 102:6954-9
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Wang, Wei; Mitra, Amit; Poole, Brian et al. (2004) Endothelial nitric oxide synthase-deficient mice exhibit increased susceptibility to endotoxin-induced acute renal failure. Am J Physiol Renal Physiol 287:F1044-8
Schrier, Robert W; Wang, Wei (2004) Acute renal failure and sepsis. N Engl J Med 351:159-69

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