Low-dose hydralazine reduces albuminuria and glomerulosclerosis in a mouse model of obesity-related chronic kidney disease.
2022
Larkin, BP | Nguyen, LT | Hou, M | Glastras, SJ | Chen, H | Faiz, A | Chen, J | Wang, R | Pollock, CA | Saad, S
BACKGROUND: Obesity is a major risk factor for the development and progression of chronic kidney disease (CKD). DNA methylation has been implicated in the progression of CKD to end stage kidney disease. Drugs modifying DNA methylation, such as low-dose hydralazine, may reduce CKD progression. Using a mouse model of obesity, we aimed to determine whether low-dose hydralazine prevents obesity-related CKD. METHODS: From 8 weeks of age, male C57BL/6 mice received high fat diet (HFD) or chow, with or without low-dose hydralazine (25 mg/L) in drinking water for 24 weeks. Biometric and metabolic parameters, renal functional and structural changes, renal global DNA methylation, DNA methylation profile and markers of renal fibrosis, injury, inflammation and oxidative stress were assessed. RESULTS: HFD-fed mice developed obesity, with glucose intolerance, hyperinsulinaemia and dyslipidaemia. Obesity increased albuminuria and glomerulosclerosis, which were significantly ameliorated by low-dose hydralazine in the absence of a blood pressure-lowering effect. Obesity increased renal global DNA methylation and this was attenuated by low-dose hydralazine. HFD-induced changes in methylation of individual loci were also significantly reversed by low-dose hydralazine. Obese mice demonstrated increased markers of kidney fibrosis, inflammation and oxidative stress, but these markers were not significantly improved by hydralazine. CONCLUSION: Low-dose hydralazine ameliorated HFD-induced albuminuria and glomerulosclerosis, independent of alterations in biometric and metabolic parameters or blood pressure regulation. Although the precise mechanism of renoprotection in obesity is unclear, an epigenetic basis may be implicated. These data support repurposing hydralazine as a novel therapy to prevent CKD progression in obese patients. This article is protected by copyright. All rights reserved.
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