This grant examines the role of the complement system in the development of ischemic acute renal failure. Our published work demonstrates that complement activation contributes to renal injury after ischemia/reperfusion (I/R), and that activation occurs primarily through the alternative pathway. The alternative pathway has emerged, in recent years, as a critical mediator of injury in a number of different diseases. This system is effective at rapidly eliminating invasive pathogens, but insufficient control of the activating enzymes permits inflammatory injury of host cells. The primary hypothesis of this grant is that hypoxia alters the surface expression of complement inhibitory proteins by proximal tubular epithelial cells. This changes the cells from a complement inhibitory to a complement activating phenotype. Once activated, the alternative pathway triggers generation of pro-inflammatory signals, including C3a, C5a, macrophage inflammatory protein-2 (MIP-2) and keratinocyte derived chemokine (KC). To test this hypothesis we will use in vivo and in vitro models to determine whether the loss of surface inhibition is sufficient to cause spontaneous alternative pathway activation, and the mechanisms by which this surface inhibition is lost after I/R (SA1). Factor H is a potent alternative pathway inhibitor that circulates in high concentrations but fails to prevent alternative pathway mediated injury in certain diseases. We will also examine whether a novel complement inhibitor that targets factor H to the site of complement activation prevents pathological complement activation after renal I/R, and the factors that modulate protection of this surface by endogenous factor H (SA2). Finally, we will examine the mechanisms by which alternative pathway activation in the tubulointerstitium triggers a widespread inflammatory response (SA3). Ischemic acute renal failure is one of the most common causes of acute renal failure, and is associated with a mortality rate of greater than 50% in the intensive care unit setting. A number of complement inhibitors have become available, including a specific inhibitor of the alternative pathway that has been developed by our laboratory and a targeted inhibitor of the alternative pathway that was developed by one of our collaborators. The proposed studies should help delineate the benefits and limitations of complement inhibition as a therapy for ischemic acute renal failure, as well as expand our understanding of complement activation as a mediator of inflammation after renal tubular injury.

Public Health Relevance

Ischemic acute renal failure is one of the most common causes of acute renal failure, and is associated with a mortality rate of greater than 50% in the intensive care unit setting. Studies have demonstrated that the complement system is activated within the kidney after ischemia. The proposed experiments examine the complex interactions between the complement system and the kidney. These studies will identify therapies that effectively inhibit the complement system and determine whether these agents will ameliorate ischemic acute renal failure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK076690-04
Application #
8105421
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Kimmel, Paul
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$305,409
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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