1. Vegfa promoter gene hypermethylation at HIF1α binding site is an early contributor to CKD progression after renal ischemia
- Author
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Norma A. Bobadilla, Andrea Sánchez-Navarro, Gerardo Gamba, Félix Recillas-Targa, Jesús Rafael Rodríguez-Aguilera, Rosalba Pérez-Villalva, Adrián Rafael Murillo-de-Ozores, María Castañeda-Bueno, Norma González, and Miguel Angel Martinez-Rojas
- Subjects
Male ,Vascular Endothelial Growth Factor A ,0301 basic medicine ,medicine.medical_specialty ,Physiology ,Science ,medicine.medical_treatment ,030232 urology & nephrology ,Pathogenesis ,Kidney ,urologic and male genital diseases ,medicine.disease_cause ,Article ,03 medical and health sciences ,0302 clinical medicine ,Ischemia ,Fibrosis ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Renal Insufficiency, Chronic ,Promoter Regions, Genetic ,Multidisciplinary ,Renal ischemia ,business.industry ,Acute kidney injury ,Acute Kidney Injury ,DNA Methylation ,Hypoxia (medical) ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,female genital diseases and pregnancy complications ,Nephrectomy ,Rats ,Oxidative Stress ,Vascular endothelial growth factor A ,030104 developmental biology ,Endocrinology ,Nephrology ,Disease Progression ,Medicine ,medicine.symptom ,business ,Oxidative stress ,Kidney disease - Abstract
Chronic hypoxia is a major contributor to Chronic Kidney Disease (CKD) after Acute Kidney Injury (AKI). However, the temporal relation between the acute insult and maladaptive renal response to hypoxia remains unclear. In this study, we analyzed the time-course of renal hemodynamics, oxidative stress, inflammation, and fibrosis, as well as epigenetic modifications, with focus on HIF1α/VEGF signaling, in the AKI to CKD transition. Sham-operated, right nephrectomy (UNx), and UNx plus renal ischemia (IR + UNx) groups of rats were included and studied at 1, 2, 3, or 4 months. The IR + UNx group developed CKD characterized by progressive proteinuria, renal dysfunction, tubular proliferation, and fibrosis. At first month post-ischemia, there was a twofold significant increase in oxidative stress and reduction in global DNA methylation that was maintained throughout the study. Hif1α and Vegfa expression were depressed in the first and second-months post-ischemia, and then Hif1α but not Vegfa expression was recovered. Interestingly, hypermethylation of the Vegfa promoter gene at the HIF1α binding site was found, since early stages of the CKD progression. Our findings suggest that renal hypoperfusion, inefficient hypoxic response, increased oxidative stress, DNA hypomethylation, and, Vegfa promoter gene hypermethylation at HIF1α binding site, are early determinants of AKI-to-CKD transition.
- Published
- 2021