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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

HIF-1α expression in diabetic nephropathy. HIF-1α immunostaining in formalin-fixed, paraffin-embedded renal biopsy tissues from patients with diabetic nephropathy (DN). (A) Shown are non-affected control kidney tissue (nl. +, less than 25% of tubular epithelial cells are stained) and kidney tissue from a patient with severe DN (DN +++, positive staining is detected in >50% of tubular epithelial cells). Arrows highlight cells with nuclear HIF-1α staining. (B) Summary of HIF-1α expression analysis in DN. DN cases are grouped according to tubulointerstitial injury score as previously described [53]. The number of biopsies with glomerular (gl) or tubular staining (t) is shown in brackets. -, absence of staining; +: 1-25% of cells per visual field with staining; ++: >25-50% and +++: >50% of cells with positive staining.
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Figure 2: HIF-1α expression in diabetic nephropathy. HIF-1α immunostaining in formalin-fixed, paraffin-embedded renal biopsy tissues from patients with diabetic nephropathy (DN). (A) Shown are non-affected control kidney tissue (nl. +, less than 25% of tubular epithelial cells are stained) and kidney tissue from a patient with severe DN (DN +++, positive staining is detected in >50% of tubular epithelial cells). Arrows highlight cells with nuclear HIF-1α staining. (B) Summary of HIF-1α expression analysis in DN. DN cases are grouped according to tubulointerstitial injury score as previously described [53]. The number of biopsies with glomerular (gl) or tubular staining (t) is shown in brackets. -, absence of staining; +: 1-25% of cells per visual field with staining; ++: >25-50% and +++: >50% of cells with positive staining.

Mentions: A discrepancy between oxygen availability and demand has been demonstrated in experimental CKD. In order to investigate the expression levels of HIF-1α in tissues from patients with CKD, we have used immunohistochemistry to analyze archival, paraffin-embedded renal biopsy material from patients with different stages of diabetic nephropathy, which is the leading cause of end stage renal disease. We found a statistically significant correlation of disease stage with the percentage of HIF-1α-expressing tubular epithelial cells, which suggested that the level of hypoxia in diabetic CKD associates with disease severity, extent of fibrosis and disease progression (Figure 2) [5]. HIF-1α was also detected in fibrotic areas of renal tissues from patients with IgA nephropathy [5]. Genome-wide gene expression analysis of micro-dissected renal biopsy material from patients with diabetic nephropathy (tubulointerstitium only) revealed that approximately 50 of 1349 differentially regulated genes were established or putative HIF transcriptional targets [5]. Increased expression was found for phosphoglycerate kinase-1 (PGK-1), chemokine receptor CXCR4, lysyl oxidase-like 2 (LOXL2) and phosphofructokinase (PFKFB3). A comparable increase in LOXL2 expression was also seen by real-time PCR in micro-dissected tubulointerstitium from patients with IgA nephropathy and hypertensive nephrosclerosis (Figure 3), suggesting a general association between LOXL2 expression and the presence of CKD [5]. Taken together with studies in experimental animal models, our clinical findings provide strong evidence that activation of the HIF system associates with the development and progression of renal fibrosis.


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

Haase VH - Fibrogenesis Tissue Repair (2012)

HIF-1α expression in diabetic nephropathy. HIF-1α immunostaining in formalin-fixed, paraffin-embedded renal biopsy tissues from patients with diabetic nephropathy (DN). (A) Shown are non-affected control kidney tissue (nl. +, less than 25% of tubular epithelial cells are stained) and kidney tissue from a patient with severe DN (DN +++, positive staining is detected in >50% of tubular epithelial cells). Arrows highlight cells with nuclear HIF-1α staining. (B) Summary of HIF-1α expression analysis in DN. DN cases are grouped according to tubulointerstitial injury score as previously described [53]. The number of biopsies with glomerular (gl) or tubular staining (t) is shown in brackets. -, absence of staining; +: 1-25% of cells per visual field with staining; ++: >25-50% and +++: >50% of cells with positive staining.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: HIF-1α expression in diabetic nephropathy. HIF-1α immunostaining in formalin-fixed, paraffin-embedded renal biopsy tissues from patients with diabetic nephropathy (DN). (A) Shown are non-affected control kidney tissue (nl. +, less than 25% of tubular epithelial cells are stained) and kidney tissue from a patient with severe DN (DN +++, positive staining is detected in >50% of tubular epithelial cells). Arrows highlight cells with nuclear HIF-1α staining. (B) Summary of HIF-1α expression analysis in DN. DN cases are grouped according to tubulointerstitial injury score as previously described [53]. The number of biopsies with glomerular (gl) or tubular staining (t) is shown in brackets. -, absence of staining; +: 1-25% of cells per visual field with staining; ++: >25-50% and +++: >50% of cells with positive staining.
Mentions: A discrepancy between oxygen availability and demand has been demonstrated in experimental CKD. In order to investigate the expression levels of HIF-1α in tissues from patients with CKD, we have used immunohistochemistry to analyze archival, paraffin-embedded renal biopsy material from patients with different stages of diabetic nephropathy, which is the leading cause of end stage renal disease. We found a statistically significant correlation of disease stage with the percentage of HIF-1α-expressing tubular epithelial cells, which suggested that the level of hypoxia in diabetic CKD associates with disease severity, extent of fibrosis and disease progression (Figure 2) [5]. HIF-1α was also detected in fibrotic areas of renal tissues from patients with IgA nephropathy [5]. Genome-wide gene expression analysis of micro-dissected renal biopsy material from patients with diabetic nephropathy (tubulointerstitium only) revealed that approximately 50 of 1349 differentially regulated genes were established or putative HIF transcriptional targets [5]. Increased expression was found for phosphoglycerate kinase-1 (PGK-1), chemokine receptor CXCR4, lysyl oxidase-like 2 (LOXL2) and phosphofructokinase (PFKFB3). A comparable increase in LOXL2 expression was also seen by real-time PCR in micro-dissected tubulointerstitium from patients with IgA nephropathy and hypertensive nephrosclerosis (Figure 3), suggesting a general association between LOXL2 expression and the presence of CKD [5]. Taken together with studies in experimental animal models, our clinical findings provide strong evidence that activation of the HIF system associates with the development and progression of renal fibrosis.

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