# Molecular mechanisms regulating peripheral arterial disease pathobiology in chronic kidney disease

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $588,983

## Abstract

PROJECT SUMMARY/ABSTRACT
Peripheral artery disease (PAD) is caused by atherosclerosis in the lower extremities which leads to a
spectrum of life-altering symptomatology, including claudication, ischemic rest pain, and gangrene requiring
limb amputation. Complicating the etiology of PAD, patients typically present with comorbid conditions or risk
factors that accelerate disease evolution and substantially worsen pathology contributing to increased mortality
risk. Among these, chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases
functional capacity, and increases risk of amputation or death, however the underlying biologic mechanism(s)
are poorly understood and vastly understudied compared with other comorbidities (i.e. smoking and diabetes).
We have uncovered a novel molecular pathway that may link CKD and PAD pathobiology. We find that many
uremic metabolites, which accumulate in CKD, cause chronic activation of the aryl hydrocarbon receptor (AHR)
which leads to disruption of the mitochondrial electron transport system that exacerbates ischemic muscle
injury and impairs angiogenesis. Preliminary experiments demonstrate that genetic knockdown of the AHR is
protective against uremic toxicity, whereas expression of a constitutively active AHR causes mitochondrial
dysfunction. Thus, we propose to test the novel hypothesis that the chronic activation of the AHR pathway
results in ischemic muscle injury and impaired angiogenesis, thereby linking CKD and PAD pathobiology. This
hypothesis will be tested using muscle- and vascular-specific inducible knockout of the AHR as well as adeno-
associated virus-mediated expression of the a constitutively active AHR in pre-clinical models of CKD/PAD.
Finally, our recent human data indicate elevated AHR signaling in PAD patients with CKD. We propose to
extend these findings to establish a clinical link between muscle health/function, mitochondrial energetics, and
AHR signaling in human PAD patients. Success in these studies will provide mechanistic insight into the
impact of CKD on PAD pathobiology, and would provide a novel target for therapeutic development aimed to
treat a patient population that currently has few available options.

## Key facts

- **NIH application ID:** 10745646
- **Project number:** 5R01HL149704-05
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Terence E Ryan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $588,983
- **Award type:** 5
- **Project period:** 2019-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745646

## Citation

> US National Institutes of Health, RePORTER application 10745646, Molecular mechanisms regulating peripheral arterial disease pathobiology in chronic kidney disease (5R01HL149704-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10745646. Licensed CC0.

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