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Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy
- Source :
- The American journal of pathology
- Publication Year :
- 2010
- Publisher :
- Elsevier BV, 2010.
-
Abstract
- 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.
- Subjects :
- Adult
Male
Pathology
medicine.medical_specialty
Adolescent
Angiogenesis
Kidney Glomerulus
030232 urology & nephrology
Biology
Pathology and Forensic Medicine
Mice
Young Adult
03 medical and health sciences
0302 clinical medicine
Fibrosis
Glomerulopathy
medicine
Animals
Humans
Hypoxia
Autocrine signalling
Cells, Cultured
reproductive and urinary physiology
Aged
Oligonucleotide Array Sequence Analysis
030304 developmental biology
0303 health sciences
Nephrosclerosis
Gene Expression Profiling
Glomerulosclerosis
Middle Aged
Hypoxia (medical)
medicine.disease
nervous system diseases
3. Good health
Oxygen
nervous system
Case-Control Studies
Tubulointerstitial fibrosis
Female
Kidney Diseases
biological phenomena, cell phenomena, and immunity
medicine.symptom
Regular Articles
Subjects
Details
- ISSN :
- 00029440
- Volume :
- 176
- Database :
- OpenAIRE
- Journal :
- The American Journal of Pathology
- Accession number :
- edsair.doi.dedup.....e7678306d568d1ec18eca3466bb0f1da