Regulation of hypoxia-inducible factor in kidney disease.
Hypoxia plays a crucial role in the pathophysiology of acute kidney injury (AKI) and presumably also chronic kidney disease (CKD). Hypoxia-inducible factor (HIF) is the master transcription factor that regulates adaptive responses against hypoxia. Under hypoxic conditions, HIF activates target genes with hypoxia-responsive elements in their regulatory regions. The HIF isoforms and regulators of HIF (i.e. prolyl hydroxylases) show cell type-specific distributions. Hypoxia is observed in both ischaemic and so-called non-ischaemic forms of AKI. In addition to the acute phase, hypoxia may ensue during the recovery phase of AKI, possibly due to the oxygen-consuming processes of cell growth and proliferation for repair. Although HIF protects the kidney against AKI, intrinsic HIF activation is submaximal in AKI and further augmentation of HIF ameliorates disease manifestations. The kidney in CKD also suffers from hypoxia caused by multiple mechanisms, including sustained oxygen demands in the remaining nephrons due to maladaptive tubuloglomerular feedback. Whether HIF is chronically upregulated in CKD is contentious. Hypoxia-inducible factor activation is a promising therapeutic approach to CKD, but excessive activation of HIF may be deleterious. It is likely that there is a therapeutic window of HIF activation in chronic conditions. Under certain circumstances, animals with CKD are protected against AKI and this may be explained by non-physiological hypoxia of the kidney and subsequent HIF expression. In addition, an acute hypoxic insult may induce long-lasting changes, possibly including epigenetic modifications induced by HIF. These observations suggest a complex interaction between AKI and CKD via hypoxia and HIF activation.
Division of Nephology and Endocrinology, The University of Tokyo School of Medicine, Tokyo, Japan. mnangaku-tky@umin.ac.jp
Masaomi
M
Nangaku
Christian
C
Rosenberger
Samuel N
SN
Heyman
Kai-Uwe
KU
Eckardt
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051793:Hypoxia-Inducible Factor 1; D000099162:Endothelial PAS Domain-Containing Protein 1