Hypoxia and the HIF system in kidney disease

Abstract

The kidney is sensitive to changes in oxygen delivery. This sensitivity has the merit of facilitating the kidneys in their adjustment of erythropoietin (EPO) production to changes in oxygen supply. The main determinant of EPO synthesis is the transcriptional activity of its gene in kidneys, which is related to local oxygen tensions. Regulation of EPO production is mediated by hypoxia-inducible factor (HIF). When local oxygen tension decreases, accumulated HIF binds to the key sequence of the EPO gene, the hypoxia-responsive element (HRE), and activates transcription of EPO. HIF consists of a constitutive β-subunit and one of alternative oxygen-regulated HIF α-subunits (HIF-1α, HIF-2α, and HIF-3α), and HIF-2α is responsible for erythropoietin production. However, the high sensitivity to changes in oxygen tension also makes the kidney prone to hypoxic injury. Severe energy depletion and subsequent activation of a number of critical alterations in metabolism occurs under hypoxic conditions. Hypoxia is also a profibrogenic stimulus. In addition to ischemic acute renal failure, hypoxia can also play a crucial role in the development of nephrotoxic acute kidney injury, radiocontrast nephropathy, and acute glomerulonephritis. Furthermore, accumulating evidence suggests that chronic hypoxia is a final common pathway to end-stage kidney failure in chronic kidney disease. Given that renal hypoxia has pivotal roles on the development and progression of both acute and chronic kidney disease, hypoxia can be a valid therapeutic target for chronic kidney disease. Activation of HIF leads to expression of a variety of adaptive genes in a coordinated manner. Studies utilizing HIF-stimulating agents proved efficacy in various kidney disease models, suggesting that HIF activation is an ideal target of future therapeutic approaches.

Physiology of the Renal Interstitium

“…Decreased oxygen tension is the principal stimulus for renal Epo expression, yet Epo production decreases in CKD, which is associated with chronic hypoxia (33,34). When Epo production is impaired in the injured kidney, extrarenal sources of Epo cannot compensate for decreased Epo levels (35).…”

“…The true value of understanding mechanisms that underlie control of Epo expression may be the possible therapeutic solutions to overcome the transcriptional silencing of Epo, a hallmark of CKD (47). While hypoxia is the principal stimulus for Epo expression under physiologic conditions, Epo transcription is silenced in chronically diseased kidneys, despite the hypoxic conditions that are a hallmark of renal fibrogenesis (34).…”

Sulfatide-Reactive Natural Killer T Cells Abrogate Ischemia-Reperfusion Injury

“…HIF-1 and HIF target genes such as EPO, VEGF, and GLUT-1 are upregulated as an adaptive response to hypoxia. [32][33][34] Previous studies have demonstrated that chemical preactivation of HIF protected renal IRI and induced upregulation of HIF-target genes. 35,36 Although HIF-1␣ expression was marginally enhanced by IRI or hypoxia only in our study, NKT activation by sulfatide increased HIF-1␣ expression significantly.…”

HIF in Kidney Disease and Development

“…[71][72][73] Medullary hypoxia is an inevitable consequence of the unique architecture of the medullary vasculature that serves a countercurrent isolation function that prevents the medullary solute gradient from being dissipated and hence allows for urinary concentrating ability. 72,74,75 The antiparallel arrangement of blood vessels allows diffusional shunting of oxygen between descending arterial vasa recta and ascending venous vasa recta (countercurrent exchange). As a consequence, the oxygen tension in the renal outer medulla remains between 10 and 20 mmHg with even lower oxygen tensions in the inner medulla, whereas the cortex benefits from an oxygen tension between 30 and 50 mmHg.…”