Acute kidney injury (AKI) is a tremendous burden on human health and health care resources. Acute alterations of the kidney microvasculature significantly contribute to kidney dysfunction during AKI. In addition, there is growing evidence that chronic alterations of the kidney microvasculature following an episode of AKI are directly related to long-term kidney dysfunction and a propensity towards chronic kidney disease. There is a fundamental gap in understanding the mechanisms responsible for these acute and chronic microvascular alterations. The long term goal is to understand the cellular and molecular basis of renal microvascular alterations associated with AKI and to develop novel and specific therapeutic interventions targeting these mechanisms. The objective of this application, which is a step toward attainment of the long term goal, is to determine how matrix metalloproteinases (MMP)-2 and -9, known collectively as gelatinases, alter renal microvascular function and structure in AKI. The central hypothesis of this application is that gelatinase activation is essential for the increased microvascular permeability and increased microvascular loss observed in AKI. The central hypothesis will be tested and the overall objective of this application will be accomplished by pursuing two specific aims.
Aim 1 will test the hypothesis that gelatinase activation in cells resident to the kidney promotes increased vascular permeability in AKI through degradation of the endothelial cell contacts and breakdown of the vascular basement membrane. To accomplish this aim, multiphoton microscopy will be employed to examine in vivo alterations in microvascular permeability, endothelial cell adhesion complexes, and vascular basement membranes in animals deficient in MMP-2 or MMP-9 using a model of AKI.
Aim 2 will test the hypothesis that gelatinase activation in AKI effects long term microvascular loss via generation of angiostatic factors. To accomplish this aim, biochemical and advanced microscopic techniques will be utilized to examine alterations in microvascular density and generation of angiostatic factors in animals deficient in MMP-2 or MMP-9 using a model of AKI. This proposed work is innovative because it applies novel methods of live-animal imaging in transgenic animals. The proposed research is significant because it is expected to provide a detailed understanding of novel mechanisms for two critical microvascular alterations associated with AKI and pinpoint innovative pharmacological interventions for ameliorating the short-term and long-term consequences of AKI. Relevance to Public Health: The proposed research will have an important positive impact because it is expected to provide novel therapeutic targets for the prevention and treatment of the serious clinical syndrome of acute kidney injury, as well as, the progression to chronic kidney disease that has become increasingly appreciated to be an important long term clinical consequence of acute kidney injury.
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