# The role of mitochondrial dysfunction in ARDS after AKI

> **NIH VA IK2** · VA SAN DIEGO HEALTHCARE SYSTEM · 2021 · —

## Abstract

Acute kidney injury (AKI) occurs in 30% of critically ill veterans, and the 6-year mortality rate is greater
than 50%1,22. Interestingly, the leading causes of death in AKI are non-renal complications, and respiratory
failure is the most serious non-renal complication of AKI with a worse prognosis than all other remote organ
failures4. It is now recognized that there are mechanisms of respiratory failure in AKI beyond volume overload,
such as the development of the acute respiratory distress syndrome (ARDS)2-3. Investigating the mechanisms of
ARDS due to AKI may lead to the development of novel strategies to improve the mortality of AKI and ARDS.
 Regarding mechanistic considerations, the kidney is a highly metabolic organ in the body with an
exceptionally high mitochondrial content, therefore mitochondrial dysfunction is a key element in various forms
of AKI5,7. Mitochondrial dysfunction as seen in AKI leads to fragmented mitochondria which function as damage
associated molecular patterns (DAMPs) that propagate systemic inflammation and injury12,13. Mitochondrial
DNA (mtDNA) is the most well-described mtDAMP, and has been shown to promote innate immunity and
systemic inflammation via activation of toll-like receptor 9 (TLR9)18. MtDNA is also known to cause lung injury
when administered intravenously to healthy animals18. I hypothesize that mitochondrial dysfunction is a
mechanism of ARDS due to AKI. Specifically, 1) Mitochondrial dysfunction in AKI leads to mtDNA
fragmentation and release into circulation. 2) Circulating mtDNA released from the kidney leads to lung injury
via TLR9 activation on pulmonary cells and neutrophils. AKI patients are also twice as likely to require
mechanical ventilation compared to patients without AKI6, and mtDNA damage is a known mechanism of
ventilator induced lung injury (VILI)20. I further hypothesize that AKI increases susceptibility to VILI, and VILI
after AKI worsens lung and kidney injury by potentiating mitochondrial dysfunction in both organs.
 I will utilize the ischemia-reperfusion (IR) model of AKI to test these hypotheses. Mitochondrial
function, dynamics, autophagy, and cell death will be evaluated in the lung and kidney after IR-AKI. MtDNA
levels will be evaluated in urine, plasma, and bronchoalveolar lavage fluid (BALF). Detailed, mechanistic studies
of mtDNA on pulmonary epithelial and endothelial cells, alveolar macrophages, and neutrophils will be
performed in vitro. Intravenous and intratracheal mtDNA administration will be evaluated in C57BL/6 and
TLR9 knockout mice in vivo. Western blot, ELISA, quantitative PCR, transmission electron microscopy, FACS
analysis, lung mechanics assessments via a flexiVent® rodent ventilator, XF96 Seahorse® extracellular flux
analyzer, and FITC-inulin kinetics will be used to assess lung and kidney injury, mitochondrial function, and
mtDNA release after IR-AKI. I will also investigate response to mechanical ventilation in mice with and without
IR-AKI to evaluate th...

## Key facts

- **NIH application ID:** 10048637
- **Project number:** 5IK2BX004338-03
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Mark Lawrence Hepokoski
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10048637

## Citation

> US National Institutes of Health, RePORTER application 10048637, The role of mitochondrial dysfunction in ARDS after AKI (5IK2BX004338-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10048637. Licensed CC0.

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