a role of HIF-3 in adjusting cellular hypoxia response and its implications in progressive renal disease

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In this study, we investigated a role of hypoxia-inducible factor (HIF)-3 as a regulator of cellular hypoxia response by HIF-1. HIF-3alpha mRNA was transcriptionally up-regulated by hypoxia in a HIF-1- dependent manner. Promoter analysis revealed that HIF-3alpha is a novel HIF-1 target gene. Overexpression of HIF-3alpha in a human proximal tubular cell line, HK-2, reduced the hypoxic induction of lysyl-oxidase most significantly among other known HIF targets. Functionally, HIF-3 counteracted the disappearance of epithelial markers, such as E-cadherin, by hypoxia and inhibited the acquisition of cell migration. In immunohistochemistry, the expression of HIF-3alpha was most evident in the nuclei of tubular epithelial cells in various models of CKD representing fibrosis. In summary, results of the present study clarify the importance of HIF-3 in counteracting kidney fibrosis in the hypoxic environment.