Xanthine oxidase/NADPH oxidase inhibition by hydralazine attenuates acute kidney injury and prevents the transition of acute kidney injury to chronic kidney disease.

Abstract

AIMS:

The enhancement of inflammation and reactive oxygen species leads to the damage of renal tubular cells in acute kidney injury (AKI), and the upregulation of inflammation increases the risk of AKI being converted into chronic kidney disease (CKD). Hydralazine has shown renoprotective effects in multiple kidney diseases and was shown to be a potent xanthine oxidase (XO) inhibitor. This study aimed to investigate the mechanisms of hydralazine in ischemia-reperfusion (I/R)-stimulated renal proximal tubular epithelial cells in vitro and in AKI animals in vivo.

MAIN METHODS:

The effects of hydralazine in AKI-to-CKD transition were also evaluated. Human renal proximal tubular epithelial cells were stimulated by I/R conditions in vitro. To generate a mouse model of AKI, a right nephrectomy was performed, followed by left renal pedicle I/R using a small atraumatic clamp.

KEY FINDINGS:

In the in vitro part, hydralazine could protect renal proximal tubular epithelial cells against insults from the I/R injury through XO/NADPH oxidase inhibition. In the in vivo part, hydralazine preserved renal function in AKI mice and improved the AKI-to-CKD transition by decreasing renal glomerulosclerosis and fibrosis independently of blood pressure lowering. Furthermore, hydralazine exerted antioxidant, anti-inflammatory, and anti-fibrotic effects both in vitro and in vivo.

SIGNIFICANCE:

Hydralazine, as a XO/NADPH oxidase inhibitor, could protect renal proximal tubular epithelial cells from the insults of I/R and prevent kidney damage in AKI and AKI-to-CKD. The above experimental studies strengthen the possibility of repurposing hydralazine as a potential renoprotective agent through its antioxidative mechanisms.

• Authors: Chih-Hung Chiang, Ching Chen, Shih-Ying Fang, Su-Chu Lin, Jaw-Wen Chen, Ting-Ting Chang
• Journal: Life sciences (Life Sci) Vol. 327 Pg. 121863 (Aug 15 2023) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 37331504 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• Xanthine Oxidase
• NADPH Oxidases
• Hydralazine
• Enzyme Inhibitors

Topics

• Mice
• Humans
• Animals
• Xanthine Oxidase
• NADPH Oxidases
• Renal Insufficiency, Chronic (pathology)
• Acute Kidney Injury (drug therapy, prevention & control, pathology)
• Kidney (pathology)
• Hydralazine (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Inflammation (pathology)
• Reperfusion Injury (pathology)
• Fibrosis