# Endotoxin preconditioning as a model to uncover protective pathways in sepsis-induced renal injury.

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $375,100

## Abstract

Gram-negative sepsis remains a major cause of mortality and morbidity in hospitalized patients,
especially when complicated by acute kidney injury (AKI). The pathophysiology of AKI in sepsis continues
to be poorly understood resulting in the persistent failure of clinical therapeutic trials. Recently, we
identified a novel pathway of renal injury in sepsis involving direct interactions between filtered
endotoxin and S1 proximal tubules. This endotoxin-S1 interaction resulted in severe peroxisomal damage
and oxidative stress in downstream S2 and S3 segments. Remarkably, this pathway of injury had no
requirement for competent immune cells. In this proposal, we continue our investigation of sepsis and
AKI by examining the mechanisms of renal endotoxin preconditioning. The phenomenon of protective
preconditioning is unique in that it represents a state of resistance to the deleterious effects of
endotoxin and yet, a preserved ability to effectively contain and eliminate infections. Unraveling the
pathways involved in endotoxin tolerance has great potential for identifying potential targets that can be
used for the prevention and treatment of human sepsis. Historically, preconditioning has been
investigated in immune cells and their isolated responses to repeated endotoxin exposure. Little is
known about the mechanisms leading to tissue protection in whole organs such as the kidney. Based on
strong preliminary data, the central hypothesis of this proposal is that macrophages are essential
components of the protective pathways of preconditioning. This is a novel hypothesis because it depicts
the macrophage as an active and beneficial participant in the tolerant phenotype. In specific aim 1, we
will establish the essential role of macrophages and examine their cross-talk with renal tubules such as
the S1 segment. In specific aim 2, we will determine the metabolic and transcriptomic changes imparted
by protective macrophages on S1 tubules. We will also identify key metabolites that can be used directlt
to treat sepsis. In specific aim 3, we will examine the potential of protective macrophages to treat
sepsis in a cell transfer approach. We believe that the proposed studies, by increasing our understanding
of endotoxin preconditioning, have great translational potential and will uncover a novel and global
approach to the prevention and treatment of sepsis and sepsis-induced AKI.

## Key facts

- **NIH application ID:** 9932444
- **Project number:** 5R01DK107623-05
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Pierre C Dagher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,100
- **Award type:** 5
- **Project period:** 2016-08-25 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932444

## Citation

> US National Institutes of Health, RePORTER application 9932444, Endotoxin preconditioning as a model to uncover protective pathways in sepsis-induced renal injury. (5R01DK107623-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9932444. Licensed CC0.

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