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

Biomedicine & Pharmacotherapy

卷:151

Ching Chen¹  Hsin-Jou Lee²  Chih-Hung Chiang³  Jaw-Wen Chen⁴  Ting-Ting Chang⁴  Su-Chu Lin⁵ 

[1] Corresponding author at: Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan.;

[2] Department of Urology/Medical Research and Education, Taipei Veterans General Hospital, Yuan-Shan/Su-Ao Branch, Yi-Lan, Taiwan;

[3] School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan;

[4] Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan;

[5] Department of Urology, National Taiwan University Hospital, Taipei, Taiwan;

关键词: Diabetic nephropathy;    Hydralazine;    Inflammation;    Nuclear factor erythroid 2-related factor 2;    Reactive oxygen species;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown