Acute renal injury, which occurs as a result of a variety of pathogenic insults, leads to a serious immediate derangement in body homeostasis, and also often triggers subsequent progressive deterioration of kidney structure and function. Based on the large volume of studies conducted in this field, it is now clear that the derangements occurring in acute renal injury are the result of abnormalities at numerous sites within the nephron, including renal vessels, glomeruli, tubules and interstitium, all of which may again contain numerous cell types, both resident, circulating and/or infiltrating. Based on data from us and others, the polymorphonuclear leukocyte appears to be pivotal in determining acute renal injury. In this project the PI will investigate mechanisms through which the polymorphonuclear leukocyte (PMN) participates in damage to the glomerulus. Using in vivo rat models, several sets of studies are designed to answer the following questions: 1) What specific role do PMNs have in the glomerular dysfunction expressed in intact systems, and 2) Are these functions modulated by the fatty acid composition of the PMN and/or the resident glomerular cell, and what are the intracellular mechanisms which underlie these modulations, and 3) Do glomerular cells, particularly mesangial cells, play a role in """"""""chemoattraction"""""""" of PMNs? A series of closely related experiments with functional and structural assessments of the microcirculation will be conducted to address the above issues. In this regard PI and her associates have recently developed methodology in two areas: One is a micro-infusion technique via a first-order branch of the renal artery, which allows functional and morphological comparison between populations of glomeruli exposed to different experimental conditions within the same kidney. Thus, this technique can provide a previously unattainable sensitivity in detecting subtle biological differences. The other is a """"""""bloodless"""""""" rat model (near total exchange transfusion with a modified stroma-free hemoglobin). This allows, by selective repletion, assessment of the role of PMNs in vivo. Moreover, ex vivo experimental manipulations of the PMNs before repletion gives the opportunity to study the specific cellular mechanisms involved in their in vivo pathogenic function. In conjunction with in vitro studies, the projects aim to identify the mechanisms present in PMNs vs. glomerular cells, through which dietary fatty acid manipulation affects the glomerular pathophysiologic process.
