Antioxidation and Nrf2-mediated heme oxygenase-1 activation contribute to renal protective effects of hydralazine in diabetic nephropathy

Ting-Ting Chang; Chih-Hung Chiang; Ching Chen; Su-Chu Lin; Hsin-Jou Lee; Jaw-Wen Chen

Biomedicine & Pharmacotherapy (Jul 2022)

Antioxidation and Nrf2-mediated heme oxygenase-1 activation contribute to renal protective effects of hydralazine in diabetic nephropathy

Ting-Ting Chang,
Chih-Hung Chiang,
Ching Chen,
Su-Chu Lin,
Hsin-Jou Lee,
Jaw-Wen Chen

Affiliations

Ting-Ting Chang: Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Corresponding author at: Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Chih-Hung Chiang: Department of Urology, National Taiwan University Hospital, Taipei, Taiwan; Department of Urology/Medical Research and Education, Taipei Veterans General Hospital, Yuan-Shan/Su-Ao Branch, Yi-Lan, Taiwan
Ching Chen: Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Su-Chu Lin: Department of Urology/Medical Research and Education, Taipei Veterans General Hospital, Yuan-Shan/Su-Ao Branch, Yi-Lan, Taiwan
Hsin-Jou Lee: Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Jaw-Wen Chen: Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan; Corresponding author at: Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan.

Journal volume & issue: Vol. 151
p. 113139

Abstract

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Reactive oxygen species (ROS) and oxidative stress are associated with the progression of diabetic nephropathy (DN). Hydralazine is an antihypertensive agent and may act as a xanthine oxidase (XO) inhibitor to reduce uric acid levels in a mouse renal injury model. This study aimed to investigate the potential mechanisms of hydralazine in experimental DN. Streptozotocin-induced diabetic mice were fed a high-fat diet to generate DN. Human renal proximal tubular epithelial cells were used in vitro. Nitrendipine and allopurinol which can reduce blood pressure or XO activity levels, were used as two positive controls. Hydralazine downregulated NF-κB/p38 signaling pathways and reduced TNF-α/IL-6 expressions in high glucose-stimulated renal proximal tubular epithelial cells. Hydralazine reduced in vitro ROS production via XO inhibition and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated heme oxygenase (HO)-1 activation. Furthermore, hydralazine reduced high glucose-induced apoptosis by downregulating PARP/caspase-3 signaling. Hydralazine and allopurinol but not nitrendipine reduced serum uric acid levels and systemic inflammation. Hydralazine and allopurinol treatment improved renal function with decreased urinary albumin-to-creatinine ratios, glomerular hypertrophy, glomerulosclerosis, and fibrosis in the kidney of DN mice. While both hydralazine and allopurinol downregulated XO and NADPH oxidase expression, only hydralazine upregulated Nrf2/HO-1 renal expression, suggesting the additional effects of hydralazine independent of XO/ NADPH oxidase inhibition. In conclusion, hydralazine protected renal proximal tubular epithelial cells against the insults of high glucose and prevented renal damage via XO/NADPH oxidase inhibition and Nrf-2/HO-1 activation, suggesting the comprehensive antioxidation and anti-inflammation mechanisms for the management of DN.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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