Dr Long The Nguyen1, Dr Benjamin P Larkin1, Dr Miao Hou2, Dr Sarah J. Glastras3, Prof Hui Chen4, Dr Alen Faiz4, Jason Chen5, Rosy Wang1, Prof Carol Pollock1, Prof Sonia Saad1
1Renal Research, Kolling Institute, University of Sydney, Sydney,, Sydney, Australia, 2Department of Cardiology, Children’s Hospital of Soochow University, Suzhou, China, 3Department of Diabetes, Endocrinology and Metabolism, Royal North Shore Hospital, Sydney, Australia, 4School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, Australia, 5Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Australia
Background: Obesity is a major risk factor of chronic kidney disease (CKD). Epigenetic modifications, particularly DNA methylation, have been implicated in the development and progression of CKD. Drugs modifying DNA methylation, such as low-dose hydralazine, may reduce CKD progression.
Aim: Using a mouse model of obesity, we aimed to determine whether low-dose hydralazine prevents obesity-related CKD.
Methods: Male C57BL/6 mice (8 weeks old) were fed a high fat diet (HFD) or chow and treated with low-dose hydralazine (25 mg/L) or drinking water for 24 weeks. Markers of metabolic disorders, kidney dysfunction and injury were examined. Renal global DNA methylation was measured and DNA methylation profile was characterised by Reduced Bisulfide Sequencing.
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 led to 63 hypomethylated and 46 hypermethylated loci in the kidneys of HFD-fed mice, while hydralazine treatment resulted in 62 hypomethylated and 83 hypermethylated loci with enrichment of cell junction organisation process. Receptor-interacting serine-threonine kinase 3 (Ripk3), a fibrotic marker, was hypomethylated in association with increased mRNA expression by HFD. Such effect was reversed by 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. 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.
Biography:
Dr. Long The Nguyen is a postdoctoral researcher in the Renal Research group at Kolling Institute and MTPConnect REDI Fellow. He has a background in cancer research, metabolic disorders, cognitive disorders, fetal programming, and kidney disease. He is working closely with Pharmaxis, an Australian Pharmaceutical company, to develop treatments for kidney fibrosis.