Abstract
A discrepancy between oxygen availability and demand has been found in most chronic kidney diseases (CKD) irrespective of etiology. This results from a combination of structural and functional changes that are commonly associated with the development of fibrosis, which include a reduction in peritubular blood flow, luminal narrowing of atherosclerotic vessels, capillary rarefaction and vascular constriction due to altered expression of vasoactive factors and signaling molecules (e.g. angiotensin II, endothelin, nitric oxide). Consistent with decreased renal oxygenation in CKD is the increased expression of the oxygen-sensitive α-subunit of hypoxia-inducible factor (HIF)-1. HIF transcription factors are members of the Per-ARNT-Sim (PAS) family of heterodimeric basic helix-loop-helix transcription factors and consist of an oxygen-sensitive α-subunit and a constitutively expressed β-unit, also known as the aryl-hydrocarbon-receptor nuclear translocator (ARNT) or HIF-β. Recent experimental evidence suggests that prolonged activation of HIF signaling in renal epithelial cells enhances maladaptive responses, which lead to fibrosis and further tissue destruction. Cell type-specific functions of individual HIF transcription factors and their relevant transcriptional targets are discussed in the context of renal fibrogenesis.
Highlights
Despite the very large blood flow (~20% of total cardiac output), the kidneys, which carry out complex and energy consuming cellular transport functions, operate under markedly reduced oxygen tension, with regional oxygen levels ranging from 10 to 60 mmHg
We found a statistically significant correlation of disease stage with the percentage of hypoxia-inducible factor (HIF)-1a-expressing tubular epithelial cells, which suggested that the level of hypoxia in diabetic chronic kidney diseases (CKD) associates with disease severity, extent of fibrosis and disease progression (Figure 2) [5]
Increased expression was found for phosphoglycerate kinase-1 (PGK-1), chemokine receptor CXCR4, lysyl oxidase-like 2 (LOXL2) and phosphofructokinase (PFKFB3)
Summary
Despite the very large blood flow (~20% of total cardiac output), the kidneys, which carry out complex and energy consuming cellular transport functions, operate under markedly reduced oxygen tension, with regional oxygen levels ranging from 10 to 60 mmHg. A reduction in renal oxygenation occurs in most chronic kidney diseases (CKD) irrespective of etiology This is due to a combination of several pathophysiological and morphologic changes, which are typically associated with chronic kidney injury. The heterodimeric basic helix-loop-helix transcription factors HIF-1 and HIF-2 are key mediators of cellular adaptation to hypoxia, and belong to the PAS {PER/aryl-hydrocarbon-receptor nuclear translocator (ARNT)/single minded (SIM)} family of transcription factors They consist of an oxygen-sensitive a-subunit and a constitutively expressed b-subunit, which is known as the aryl hydrocarbon receptor nuclear translocator (ARNT), and facilitate both oxygen delivery and cell survival by stimulating erythropoiesis, angiogenesis and anaerobic energy metabolism. Our laboratory has identified epithelial HIF-1a as a promoter of kidney fibrosis, and has demonstrated that HIF-1 activation stimulates collagen accumulation and inflammatory cell recruitment in experimental models of CKD [5,15]
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