Nephrology

Tubulointerstitial hypoxia plays an essential role as the final common pathway to end-stage renal disease. Hypoxia-Inducible Factor (HIF) is a master transcriptional factor responsible for tissues to adapt to the environment of reduced oxygen concentration. Such mechanisms include regulation of downstream target genes involved in angiogenesis, erythropoiesis and anaerobic metabolism. In some pathophysiological contexts, hypoxia may be recorded as epigenetic changes (“hypoxic memory”) and be responsible for the progression of the kidney disease in the long term. In this regard, we performed genome-wide analysis of HIF-1 binding sites using high-throughput sequencers and found novel downstream targets relevant to epithelial cell behavior. By simultaneously checking histone modification marks, we identified novel roles of HIF-1 in histone modification which enhances its target gene expression. Furthermore, microarray analysis and RNA-seq in cultured tubular cells exposed to hypoxia demonstrated the expression of several novel long non-coding RNA (lncRNA), including aspartyltRNA synthase anti-sense 1 (DARS-AS1), which was most strongly induced by hypoxia and suggested to play anti-apoptotic roles. In an AKI to CKD transition model of ischemia-reperfusion injury in vivo, we observed that pharmacological targeting of histone modifications was effective in ameliorating fibrosis. In summary, HIF is responsible for a variety of epigenetic changes and may ultimately determine the consequences of the disease phenotypes.