The uremic toxin hippurate promotes endothelial dysfunction via the activation of Drp1-mediated mitochondrial fission.

Abstract

The accumulation of uremic toxins in chronic kidney disease (CKD) induces inflammation, oxidative stress and endothelial dysfunction, which is a key step in atherosclerosis. Accumulating evidence indicates increased mitochondrial fission is a contributing mechanism for impaired endothelial function. Hippurate, a uremic toxin, has been reported to be involved in cardiovascular diseases. Here, we assessed the endothelial toxicity of hippurate and the contribution of altered mitochondrial dynamics to hippurate-induced endothelial dysfunction. Treatment of human aortic endothelial cells with hippurate reduced the expression of endothelial nitric oxide synthase (eNOS) and increased the expression of intercellular cell adhesion molecule-1 (ICAM-1) and von Willebrand factor (vWF). The mechanisms of hippurate-induced endothelial dysfunction in vitro depended on the activation of Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and overproduction of mitochondrial reactive oxygen species (mitoROS). In a rat model in which CKD was induced by 5/6 nephrectomy (CKD rat), we observed increased oxidative stress, impaired endothelium-dependent vasodilation, and elevated soluble biomarkers of endothelial dysfunction (ICAM-1 and vWF). Similarly, endothelial dysfunction was identified in healthy rats treated with disease-relevant concentrations of hippurate. In aortas of CKD rats and hippurate-treated rats, we observed an increase in Drp1 protein levels and mitochondrial fission. Inhibition of Drp1 improved endothelial function in both rat models. These results indicate that hippurate, by itself, can cause endothelial dysfunction. Increased mitochondrial fission plays an active role in hippurate-induced endothelial dysfunction via an increase in mitoROS.

• Authors: Mengjie Huang, Ribao Wei, Yang Wang, Tingyu Su, Ping Li, Xiangmei Chen
• Journal: Redox biology (Redox Biol) Vol. 16 Pg. 303-313 (06 2018) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 29573704 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Hippurates
• Microtubule-Associated Proteins
• Mitochondrial Proteins
• Reactive Oxygen Species
• von Willebrand Factor
• Intercellular Adhesion Molecule-1
• NOS3 protein, human
• Nitric Oxide Synthase Type III
• GTP Phosphohydrolases
• DNM1L protein, human
• Dynamins
• hippuric acid

Topics

• Animals
• Aorta (cytology, drug effects)
• Atherosclerosis (genetics, metabolism)
• Dynamins
• Endothelial Cells (drug effects, pathology)
• GTP Phosphohydrolases (genetics, metabolism)
• Gene Expression Regulation (drug effects)
• Hippurates (metabolism, pharmacology)
• Humans
• Inflammation (metabolism, pathology)
• Intercellular Adhesion Molecule-1 (genetics)
• Microtubule-Associated Proteins (genetics, metabolism)
• Mitochondrial Dynamics (drug effects, genetics)
• Mitochondrial Proteins (genetics, metabolism)
• Nitric Oxide Synthase Type III (genetics)
• Oxidative Stress (drug effects, genetics)
• Rats
• Reactive Oxygen Species (metabolism)
• Renal Insufficiency, Chronic (genetics, metabolism, pathology)
• von Willebrand Factor (genetics)