Eicosanoids are biologically active products of phospholipid metabolism which are involved in the pathogenesis of numerous autoimmune and inflammatory diseases in humans. Published data has implicated that eicosanoids derived from the microsomal Prostaglandin Synthase type 1 (mPGES-1) and 15-Lipoxygenase (12/15-LOX) enzymes are involved in mediating tissue injury in multiple different cell types including epithelial cells and bone marrow derived monocytes (BMDMs). Of note, mPGES-1 and 12/15-LOX are thought to be critical mediators of kidney damage in many different animal models of acute and chronic renal diseases. In order to develop novel therapeutic approaches to treat kidney disease, in particular chronic kidney disease (CKD), a better understanding of how eicosanoids are produced among specific cell types in the disease renal microenvironment is urgently needed. Our overall hypothesis is that mPGES-1 and 12/15-LOX-derived products from both resident cells and recruited inflammatory cells are instrumental in pathways that control renal epithelial injury, inflammation, and fibrosis during UUO; and that manipulating the balance of these eicosanoids by genetic or pharmacologic means is a viable therapy to modify renal disease progressions This proposal seeks to test this hypothesis using a bone marrow transplantation approach to generate mice chimeric for mPGES-1 and 12/15-LOX expression. These mice will undergo unilateral ureteral obstruction (UUO), a model of renal fibrosis; and chronic folic acid nephropathy, a model of fibrosis and CKD progression. Renal tissue injury and renal failure will be quantified using standardized as well as cutting edge techniques. We will employ state of the art microscopy, flow cytometry, transcriptional profiling, and lipidomic analysis in our studies. We will compare how targeted deletion of mPGES-1 and 12/15-LOX from infiltrating bone marrow-derived cells and from resident cell types influence renal injury and CKD progression. Additionally, we will study the effects of these two pathways in a novel cell culture in-vitro model using monocytes and renal epithelial cells isolated directly from genetically altered mice. We will examine how cell- specific expression of these enzymes and products in monocytes and epithelial cells influences downstream molecular pathways which will be further altered using experimental chemical agents. These studies will provide solid mechanistic evidence for novel therapeutic approaches to treat humans with kidney disease.
Chronic Kidney Disease (CKD) is major burden to global health systems and responsible for a disproportionate amount of patient morbidity, mortality, and strain within the Veterans Health Administration. Increasing knowledge of the basic biology of CKD holds the promise to unlock new therapies to halt or reverse kidney fibrosis, a pathologic finding that is responsible for CKD progression in humans. Our proposal seeks to better define the role of eicosanoids, which are potent inflammatory molecules that appear to play a major role in driving chronic inflammation that is directly linked to kidney fibrosis and CKD progression. We plan to use animal models of CKD, genetically altered mice, drug therapies, advanced imaging technology, and other highly sophisticated tools in order to determine how we can exploit certain eicosanoid targets for future drug therapy development in humans.
