Human nephrosclerosis triggers a hypoxia-related glomerulopathy
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Human nephrosclerosis triggers a hypoxia-related glomerulopathy. / Neusser, Matthias A; Lindenmeyer, Maja T; Moll, Anton G; Segerer, Stephan; Edenhofer, Ilka; Sen, Kontheari; Stiehl, Daniel P; Kretzler, Matthias; Gröne, Hermann-Josef; Schlöndorff, Detlef; Cohen, Clemens D.
in: AM J PATHOL, Jahrgang 176, Nr. 2, 02.2010, S. 594-607.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Human nephrosclerosis triggers a hypoxia-related glomerulopathy
AU - Neusser, Matthias A
AU - Lindenmeyer, Maja T
AU - Moll, Anton G
AU - Segerer, Stephan
AU - Edenhofer, Ilka
AU - Sen, Kontheari
AU - Stiehl, Daniel P
AU - Kretzler, Matthias
AU - Gröne, Hermann-Josef
AU - Schlöndorff, Detlef
AU - Cohen, Clemens D
PY - 2010/2
Y1 - 2010/2
N2 - In the kidney, hypoxia contributes to tubulointerstitial fibrosis, but little is known about its implications for glomerular damage and glomerulosclerosis. Chronic hypoxia was hypothesized to be involved in nephrosclerosis (NSC) or "hypertensive nephropathy." In the present study genome-wide expression data from microdissected glomeruli were studied to examine the role of hypoxia in glomerulosclerosis of human NSC. Functional annotation analysis revealed prominent regulation of hypoxia-associated biological processes in NSC, including angiogenesis, fibrosis, and inflammation. Glomerular expression levels of a majority of genes regulated by the hypoxia-inducible factors (HIFs) were significantly altered in NSC. Among these HIF targets, chemokine C-X-C motif receptor 4 (CXCR4) was prominently induced. Glomerular CXCR4 mRNA induction was confirmed by quantitative RT-PCR in an independent cohort with NSC but not in those with other glomerulopathies. By immunohistological analysis, CXCR4 showed enhanced positivity in podocytes in NSC biopsy specimens. This CXCR4 positivity was associated with nuclear localization of HIF1alpha only in podocytes of NSC, indicating transcriptional activity of HIF. As the CXCR4 ligand CXCL12/SDF-1 is constitutively expressed in podocytes, autocrine signaling may contribute to NSC. In addition, a blocking CXCR4 antibody caused significant inhibition of wound closure by podocytes in an in vitro scratch assay. These data support a role for CXCR4/CXCL12 in human NSC and indicate that hypoxia not only is involved in tubulointerstitial fibrosis but also contributes to glomerular damage in NSC.
AB - In the kidney, hypoxia contributes to tubulointerstitial fibrosis, but little is known about its implications for glomerular damage and glomerulosclerosis. Chronic hypoxia was hypothesized to be involved in nephrosclerosis (NSC) or "hypertensive nephropathy." In the present study genome-wide expression data from microdissected glomeruli were studied to examine the role of hypoxia in glomerulosclerosis of human NSC. Functional annotation analysis revealed prominent regulation of hypoxia-associated biological processes in NSC, including angiogenesis, fibrosis, and inflammation. Glomerular expression levels of a majority of genes regulated by the hypoxia-inducible factors (HIFs) were significantly altered in NSC. Among these HIF targets, chemokine C-X-C motif receptor 4 (CXCR4) was prominently induced. Glomerular CXCR4 mRNA induction was confirmed by quantitative RT-PCR in an independent cohort with NSC but not in those with other glomerulopathies. By immunohistological analysis, CXCR4 showed enhanced positivity in podocytes in NSC biopsy specimens. This CXCR4 positivity was associated with nuclear localization of HIF1alpha only in podocytes of NSC, indicating transcriptional activity of HIF. As the CXCR4 ligand CXCL12/SDF-1 is constitutively expressed in podocytes, autocrine signaling may contribute to NSC. In addition, a blocking CXCR4 antibody caused significant inhibition of wound closure by podocytes in an in vitro scratch assay. These data support a role for CXCR4/CXCL12 in human NSC and indicate that hypoxia not only is involved in tubulointerstitial fibrosis but also contributes to glomerular damage in NSC.
KW - Adolescent
KW - Adult
KW - Aged
KW - Animals
KW - Case-Control Studies
KW - Cells, Cultured
KW - Female
KW - Gene Expression Profiling
KW - Humans
KW - Hypoxia
KW - Kidney Diseases
KW - Kidney Glomerulus
KW - Male
KW - Mice
KW - Middle Aged
KW - Nephrosclerosis
KW - Oligonucleotide Array Sequence Analysis
KW - Oxygen
KW - Young Adult
KW - Journal Article
KW - Multicenter Study
KW - Research Support, N.I.H., Extramural
KW - Research Support, Non-U.S. Gov't
U2 - 10.2353/ajpath.2010.090268
DO - 10.2353/ajpath.2010.090268
M3 - SCORING: Journal article
C2 - 20019191
VL - 176
SP - 594
EP - 607
JO - AM J PATHOL
JF - AM J PATHOL
SN - 0002-9440
IS - 2
ER -
