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Hypoxia-inducible factor signaling in the development of kidney fibrosis.

Haase VH - Fibrogenesis Tissue Repair (2012)

Bottom Line: A discrepancy between oxygen availability and demand has been found in most chronic kidney diseases (CKD) irrespective of etiology.Consistent with decreased renal oxygenation in CKD is the increased expression of the oxygen-sensitive α-subunit of hypoxia-inducible factor (HIF)-1.Cell type-specific functions of individual HIF transcription factors and their relevant transcriptional targets are discussed in the context of renal fibrogenesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Nephrology and Hypertension, Departments of Medicine, Molecular Physiology and Biophysics, and Cancer Biology, Vanderbilt School of Medicine, Nashville, TN, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Overview of HIF signaling in CKD. Shown is a summary of potential mechanisms by which epithelial HIF-1 could act as a profibrotic transcription factor. These include the regulation of ECM production and processing through matrix modifying factors and enzymes, such as CTGF, PAI-1, TIMP-1 and MMPs, and the modulation of EMT triggering pathways. The role of non-epithelial HIF in the pathogenesis of renal fibrogenesis is not known. Abb.: CTGF, connective tissue growth factor; ECM, extra-cellular matrix; EMT, epithelial to mesenchymal transition; NO, nitric oxide; PAI-1, plasminogen activator inhibitor 1; ROS, reactive oxygen species; TIMP-1, tissue-inhibitor of metalloproteinase 1.
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Figure 5: Overview of HIF signaling in CKD. Shown is a summary of potential mechanisms by which epithelial HIF-1 could act as a profibrotic transcription factor. These include the regulation of ECM production and processing through matrix modifying factors and enzymes, such as CTGF, PAI-1, TIMP-1 and MMPs, and the modulation of EMT triggering pathways. The role of non-epithelial HIF in the pathogenesis of renal fibrogenesis is not known. Abb.: CTGF, connective tissue growth factor; ECM, extra-cellular matrix; EMT, epithelial to mesenchymal transition; NO, nitric oxide; PAI-1, plasminogen activator inhibitor 1; ROS, reactive oxygen species; TIMP-1, tissue-inhibitor of metalloproteinase 1.

Mentions: Our finding that HIF activation in epithelial cells promotes renal fibrosis has immediate clinical implications, as it encourages therapies that aim at improving tissue oxygenation to retard disease progression. Because HIF regulates multiple biological processes, which include erythropoiesis and iron metabolism, its systemic pharmacological inhibition is not desirable. Certain HIF regulated proteins, however, may represent better therapeutic targets to slow progression of CKD. Pharmacological inihibition of lysyl oxidases phenocopied the effects of genetic HIF-1 inactivation on cell motility and fibrogenesis, suggesting that lysyl oxidases are important contributors to the pathogenesis of renal fibrosis. In keeping with this notion, increased LOXL2 expression was found in renal biopsy tissues from patients with CKD underscoring its relevance to the pathogenesis of CKD irrespective of etiology (Figure 5). Whether pharmacological inhibition of lysyl oxidases is feasible in clinical practice to slow progression of CKD certainly warrants further investigation.


Hypoxia-inducible factor signaling in the development of kidney fibrosis.

Haase VH - Fibrogenesis Tissue Repair (2012)

Overview of HIF signaling in CKD. Shown is a summary of potential mechanisms by which epithelial HIF-1 could act as a profibrotic transcription factor. These include the regulation of ECM production and processing through matrix modifying factors and enzymes, such as CTGF, PAI-1, TIMP-1 and MMPs, and the modulation of EMT triggering pathways. The role of non-epithelial HIF in the pathogenesis of renal fibrogenesis is not known. Abb.: CTGF, connective tissue growth factor; ECM, extra-cellular matrix; EMT, epithelial to mesenchymal transition; NO, nitric oxide; PAI-1, plasminogen activator inhibitor 1; ROS, reactive oxygen species; TIMP-1, tissue-inhibitor of metalloproteinase 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368791&req=5

Figure 5: Overview of HIF signaling in CKD. Shown is a summary of potential mechanisms by which epithelial HIF-1 could act as a profibrotic transcription factor. These include the regulation of ECM production and processing through matrix modifying factors and enzymes, such as CTGF, PAI-1, TIMP-1 and MMPs, and the modulation of EMT triggering pathways. The role of non-epithelial HIF in the pathogenesis of renal fibrogenesis is not known. Abb.: CTGF, connective tissue growth factor; ECM, extra-cellular matrix; EMT, epithelial to mesenchymal transition; NO, nitric oxide; PAI-1, plasminogen activator inhibitor 1; ROS, reactive oxygen species; TIMP-1, tissue-inhibitor of metalloproteinase 1.
Mentions: Our finding that HIF activation in epithelial cells promotes renal fibrosis has immediate clinical implications, as it encourages therapies that aim at improving tissue oxygenation to retard disease progression. Because HIF regulates multiple biological processes, which include erythropoiesis and iron metabolism, its systemic pharmacological inhibition is not desirable. Certain HIF regulated proteins, however, may represent better therapeutic targets to slow progression of CKD. Pharmacological inihibition of lysyl oxidases phenocopied the effects of genetic HIF-1 inactivation on cell motility and fibrogenesis, suggesting that lysyl oxidases are important contributors to the pathogenesis of renal fibrosis. In keeping with this notion, increased LOXL2 expression was found in renal biopsy tissues from patients with CKD underscoring its relevance to the pathogenesis of CKD irrespective of etiology (Figure 5). Whether pharmacological inhibition of lysyl oxidases is feasible in clinical practice to slow progression of CKD certainly warrants further investigation.

Bottom Line: A discrepancy between oxygen availability and demand has been found in most chronic kidney diseases (CKD) irrespective of etiology.Consistent with decreased renal oxygenation in CKD is the increased expression of the oxygen-sensitive α-subunit of hypoxia-inducible factor (HIF)-1.Cell type-specific functions of individual HIF transcription factors and their relevant transcriptional targets are discussed in the context of renal fibrogenesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Nephrology and Hypertension, Departments of Medicine, Molecular Physiology and Biophysics, and Cancer Biology, Vanderbilt School of Medicine, Nashville, TN, USA.

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.

No MeSH data available.


Related in: MedlinePlus