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.
Highlights
Clinical, epidemiological, and experimental studies have shown that Acute Kidney Injury (AKI) is an independent risk factor for the development of Chronic Kidney Disease (CKD) and end-stage renal disease (ESRD)[1,2]
In AKI, obstructive renal injury, and diabetic nephropathy, epigenetic modifications induced an increase in proinflammatory and profibrotic cytokines such as monocyte chemoattractant protein-1 (MCP-1), complement protein 3 (C3), transforming growth factor β (TGF-β), which in turn perpetuate inflammation and promote epithelial-to-mesenchymal transition (EMT) that contributes to renal fibrosis[34,35,36,37,38]
After 24 h of inducing renal ischemia, all the ischemia/ reperfusion (IR) + UNx rats exhibited significant proteinuria that was of the same magnitude among the groups assigned to 1, 2, 3 and, 4 months of follow-up (Fig. 1A), together with a similar reduction in renal function (Fig. 1B); these alterations were not observed in the S (n = 16) or UNx (n = 16) groups after 24 h of the surgery as is shown by the individual data presented in Fig. 1A, B
Summary
Epidemiological, and experimental studies have shown that AKI is an independent risk factor for the development of CKD and end-stage renal disease (ESRD)[1,2]. After an AKI episode, a cascade of events occurs, such as brush border loss, cell polarity alterations, increased oxidative stress, and mitochondrial dysfunction of proximal tubular epithelial cells[7,8], as a result, some of these cells undergo necrosis or apoptosis[9]. These processes are accompanied by macrophage infiltration and inflammation[7,10,11]. We found abnormal renal hemodynamics, reduced HIF-1α signaling, increased oxidative stress, and global DNA hypomethylation in the early phase of the AKI to CKD transition. We showed that the HIF-1α/Vegfa signaling reduction was associated with the DNA hypermethylation of the Vegfa gene promoter, beginning at an early stage post-ischemia and suggesting that reduced VEGF expression is an early contributor that triggers renal hypoxia and the consequent fibrosis
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