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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 PHD/HIF signaling. Under normoxia, both HIF-1α and HIF-2α are hydroxylated by prolyl-4-hydroxylases and are targeted for proteasomal degradation by the von Hippel-Lindau (pVHL)-E3 ubiquitin ligase complex (shown are key components of this complex). Binding to prolyl-hydroxylated HIF-α occurs at the β-domain of pVHL, which spans amino acid residues 64 - 154. The C-terminal α-domain links the substrate recognition component pVHL to the E3 ubiquitin ligase via elongin C. When prolyl-4-hydroxylation is inhibited (e.g. by hypoxia, ROS), HIF-α subunits are stabilized and translocate to the nucleus where they heterodimerize with ARNT. HIF-α/ARNT heterodimers bind to the HIF consensus-binding site, RCGTG, resulting in increased expression of target genes. Factor-inhibiting-HIF (FIH) is a dioxygenase that modulates transcriptional cofactor recruitment (CBP/p300) via asparagine (Asn) hydroxylation of the HIF-α carboxy-terminal transactivation domain. In addition to ROS, nitric oxide, Krebs cycle metabolites succinate and fumarate, cobalt chloride and iron chelators such as desferrioxamine inhibit HIF prolyl-4-hydroxylases in the presence of oxygen. Abb.: CoCl2, cobalt chloride; Fe2+, ferrous iron; NO, nitric oxide; PHI, prolyl-4-hydroxylase inhibitors (structural 2-oxoglutarate analogs); ROS, reactive oxygen species; ub, ubiquitin.
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Figure 1: Overview of PHD/HIF signaling. Under normoxia, both HIF-1α and HIF-2α are hydroxylated by prolyl-4-hydroxylases and are targeted for proteasomal degradation by the von Hippel-Lindau (pVHL)-E3 ubiquitin ligase complex (shown are key components of this complex). Binding to prolyl-hydroxylated HIF-α occurs at the β-domain of pVHL, which spans amino acid residues 64 - 154. The C-terminal α-domain links the substrate recognition component pVHL to the E3 ubiquitin ligase via elongin C. When prolyl-4-hydroxylation is inhibited (e.g. by hypoxia, ROS), HIF-α subunits are stabilized and translocate to the nucleus where they heterodimerize with ARNT. HIF-α/ARNT heterodimers bind to the HIF consensus-binding site, RCGTG, resulting in increased expression of target genes. Factor-inhibiting-HIF (FIH) is a dioxygenase that modulates transcriptional cofactor recruitment (CBP/p300) via asparagine (Asn) hydroxylation of the HIF-α carboxy-terminal transactivation domain. In addition to ROS, nitric oxide, Krebs cycle metabolites succinate and fumarate, cobalt chloride and iron chelators such as desferrioxamine inhibit HIF prolyl-4-hydroxylases in the presence of oxygen. Abb.: CoCl2, cobalt chloride; Fe2+, ferrous iron; NO, nitric oxide; PHI, prolyl-4-hydroxylase inhibitors (structural 2-oxoglutarate analogs); ROS, reactive oxygen species; ub, ubiquitin.

Mentions: HIF heterodimers activate gene transcription in response to hypoxia by binding to specific DNA sequences, which are known as hypoxia-response elements (HREs) and by recruiting transcriptional co-activators such as CBP/p300 (Figure 1). While HIF-α is continuously synthesized, it is rapidly degraded under normoxia, keeping HIF signaling at minimal levels when oxygen tension is in normal range. HIF degradation under normoxia requires hydroxylation of specific proline residues within the oxygen-dependent degradation domain of HIF-α, enabling interaction with the von Hippel-Lindau tumor suppressor pVHL, which functions as the substrate recognition component of an E3 ubiquitin ligase complex [13,14]. HIF hydroxylation depends on the presence of molecular oxygen, ferrous iron and ascorbate, and is carried out by 2-oxoglutarate-dependent dioxygenases (prolyl-4-hydroxylase domain (PHD) proteins). Three major HIF-hydroxylating enzymes have been identified, PHD1, 2 and 3, of which PHD2 is most important for normoxic HIF degradation [14]. A second hypoxic switch operates in the carboxy-terminal transactivation domain of HIF-α with the hydroxylation of an asparagine residue. Under hypoxic conditions asparagine hydroxylation is inhibited and CBP/p300 recruitment facilitated, enabling increased levels of transcription [14].


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

Haase VH - Fibrogenesis Tissue Repair (2012)

Overview of PHD/HIF signaling. Under normoxia, both HIF-1α and HIF-2α are hydroxylated by prolyl-4-hydroxylases and are targeted for proteasomal degradation by the von Hippel-Lindau (pVHL)-E3 ubiquitin ligase complex (shown are key components of this complex). Binding to prolyl-hydroxylated HIF-α occurs at the β-domain of pVHL, which spans amino acid residues 64 - 154. The C-terminal α-domain links the substrate recognition component pVHL to the E3 ubiquitin ligase via elongin C. When prolyl-4-hydroxylation is inhibited (e.g. by hypoxia, ROS), HIF-α subunits are stabilized and translocate to the nucleus where they heterodimerize with ARNT. HIF-α/ARNT heterodimers bind to the HIF consensus-binding site, RCGTG, resulting in increased expression of target genes. Factor-inhibiting-HIF (FIH) is a dioxygenase that modulates transcriptional cofactor recruitment (CBP/p300) via asparagine (Asn) hydroxylation of the HIF-α carboxy-terminal transactivation domain. In addition to ROS, nitric oxide, Krebs cycle metabolites succinate and fumarate, cobalt chloride and iron chelators such as desferrioxamine inhibit HIF prolyl-4-hydroxylases in the presence of oxygen. Abb.: CoCl2, cobalt chloride; Fe2+, ferrous iron; NO, nitric oxide; PHI, prolyl-4-hydroxylase inhibitors (structural 2-oxoglutarate analogs); ROS, reactive oxygen species; ub, ubiquitin.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Overview of PHD/HIF signaling. Under normoxia, both HIF-1α and HIF-2α are hydroxylated by prolyl-4-hydroxylases and are targeted for proteasomal degradation by the von Hippel-Lindau (pVHL)-E3 ubiquitin ligase complex (shown are key components of this complex). Binding to prolyl-hydroxylated HIF-α occurs at the β-domain of pVHL, which spans amino acid residues 64 - 154. The C-terminal α-domain links the substrate recognition component pVHL to the E3 ubiquitin ligase via elongin C. When prolyl-4-hydroxylation is inhibited (e.g. by hypoxia, ROS), HIF-α subunits are stabilized and translocate to the nucleus where they heterodimerize with ARNT. HIF-α/ARNT heterodimers bind to the HIF consensus-binding site, RCGTG, resulting in increased expression of target genes. Factor-inhibiting-HIF (FIH) is a dioxygenase that modulates transcriptional cofactor recruitment (CBP/p300) via asparagine (Asn) hydroxylation of the HIF-α carboxy-terminal transactivation domain. In addition to ROS, nitric oxide, Krebs cycle metabolites succinate and fumarate, cobalt chloride and iron chelators such as desferrioxamine inhibit HIF prolyl-4-hydroxylases in the presence of oxygen. Abb.: CoCl2, cobalt chloride; Fe2+, ferrous iron; NO, nitric oxide; PHI, prolyl-4-hydroxylase inhibitors (structural 2-oxoglutarate analogs); ROS, reactive oxygen species; ub, ubiquitin.
Mentions: HIF heterodimers activate gene transcription in response to hypoxia by binding to specific DNA sequences, which are known as hypoxia-response elements (HREs) and by recruiting transcriptional co-activators such as CBP/p300 (Figure 1). While HIF-α is continuously synthesized, it is rapidly degraded under normoxia, keeping HIF signaling at minimal levels when oxygen tension is in normal range. HIF degradation under normoxia requires hydroxylation of specific proline residues within the oxygen-dependent degradation domain of HIF-α, enabling interaction with the von Hippel-Lindau tumor suppressor pVHL, which functions as the substrate recognition component of an E3 ubiquitin ligase complex [13,14]. HIF hydroxylation depends on the presence of molecular oxygen, ferrous iron and ascorbate, and is carried out by 2-oxoglutarate-dependent dioxygenases (prolyl-4-hydroxylase domain (PHD) proteins). Three major HIF-hydroxylating enzymes have been identified, PHD1, 2 and 3, of which PHD2 is most important for normoxic HIF degradation [14]. A second hypoxic switch operates in the carboxy-terminal transactivation domain of HIF-α with the hydroxylation of an asparagine residue. Under hypoxic conditions asparagine hydroxylation is inhibited and CBP/p300 recruitment facilitated, enabling increased levels of transcription [14].

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