Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Av. Universidad 3000, UNAM, CU, 04510 Coyoacán,, Mexico City, Mexico.
Department of Nephrology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Tlalpan 14080, Mexico City, Mexico.
Sci Rep. 2021 Apr 22;11(1):8769. doi: 10.1038/s41598-021-88000-5.
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.
慢性缺氧是急性肾损伤 (AKI) 后慢性肾脏病 (CKD) 的主要原因。然而，急性损伤与对缺氧的适应性肾脏反应之间的时间关系仍不清楚。在这项研究中，我们分析了 AKI 向 CKD 过渡过程中肾脏血液动力学、氧化应激、炎症和纤维化的时间过程，以及表观遗传修饰，重点关注 HIF1α/VEGF 信号。包括假手术、单侧肾切除术 (UNx) 和单侧肾切除术加肾缺血 (IR+UNx) 组大鼠，并在 1、2、3 或 4 个月时进行研究。IR+UNx 组发生 CKD，表现为进行性蛋白尿、肾功能障碍、肾小管增生和纤维化。缺血后第一个月，氧化应激显著增加两倍，全基因组 DNA 甲基化减少，整个研究过程中均保持不变。Hif1α 和 Vegfa 的表达在缺血后第一个和第二个月下降，然后 Hif1α 的表达恢复，但 Vegfa 的表达没有恢复。有趣的是，在 CKD 进展的早期阶段发现 Vegfa 启动子基因在 HIF1α 结合位点发生了过度甲基化。我们的研究结果表明，肾脏低灌注、缺氧反应效率低下、氧化应激增加、DNA 低甲基化以及 Vegfa 启动子基因在 HIF1α 结合位点的过度甲基化是 AKI 向 CKD 过渡的早期决定因素。
