# The Role of Bone Marrow Derived Eicosanoids in Renal Disease Progression

> **NIH VA IK2** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2020 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 9898241
- **Project number:** 5IK2BX003839-03
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** John Ross Montford
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898241

## Citation

> US National Institutes of Health, RePORTER application 9898241, The Role of Bone Marrow Derived Eicosanoids in Renal Disease Progression (5IK2BX003839-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898241. Licensed CC0.

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