Novel Therapeutic Strategy With Hypoxia-Inducible Factors via Reversible Epigenetic Regulation Mechanisms in Progressive Tubulointerstitial Fibrosis

Hypoxia-inducible factor (HIF) is a transcriptional master regulator that takes control of the gene expressions under hypoxia. Several lines of evidence have shown that chronic hypoxia in tubulointerstitium results in irreversible renal disease. Recently, HIF1 was reported to organize a cluster of histone-modifying enzymes by binding to their promoter regions in various kinds of cell lines. However, its function in renal disease remains largely unknown. We focused on the epigenetic regulation on the progression of chronic kidney disease and have reviewed the latest knowledge in this area with special emphasis on the involvement of HIF. For example, a set of HIF1 downstream target genes also were reported to be regulated by cooperative combination of HIF1 and histone demethylase. We suggest a novel epigenetic pathway that affects the final common pathway to end-stage renal disease in addition to the tubulointerstitial hypoxia. We emphasize the importance of figuring out the epigenetic mechanisms of renal failure to find the novel therapeutic approach of chronic kidney disease.