SDF-1/CXCR4 signaling preserves microvascular integrity and renal function in chronic kidney disease.
The progressive decline of renal function in chronic kidney disease (CKD) is characterized by both disruption of the microvascular architecture and the accumulation of fibrotic matrix. One angiogenic pathway recently identified as playing an essential role in renal vascular development is the stroma...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3956917?pdf=render |
| _version_ | 1818942436668342272 |
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| author | Li-Hao Chen Suzanne L Advani Kerri Thai M Golam Kabir Manish M Sood Ian W Gibson Darren A Yuen Kim A Connelly Philip A Marsden Darren J Kelly Richard E Gilbert Andrew Advani |
| author_facet | Li-Hao Chen Suzanne L Advani Kerri Thai M Golam Kabir Manish M Sood Ian W Gibson Darren A Yuen Kim A Connelly Philip A Marsden Darren J Kelly Richard E Gilbert Andrew Advani |
| author_sort | Li-Hao Chen |
| collection | DOAJ |
| description | The progressive decline of renal function in chronic kidney disease (CKD) is characterized by both disruption of the microvascular architecture and the accumulation of fibrotic matrix. One angiogenic pathway recently identified as playing an essential role in renal vascular development is the stromal cell-derived factor-1α (SDF-1)/CXCR4 pathway. Because similar developmental processes may be recapitulated in the disease setting, we hypothesized that the SDF-1/CXCR4 system would regulate microvascular health in CKD. Expression of CXCR4 was observed to be increased in the kidneys of subtotally nephrectomized (SNx) rats and in biopsies from patients with secondary focal segmental glomerulosclerosis (FSGS), a rodent model and human correlate both characterized by aberration of the renal microvessels. A reno-protective role for local SDF-1/CXCR4 signaling was indicated by i) CXCR4-dependent glomerular eNOS activation following acute SDF-1 administration; and ii) acceleration of renal function decline, capillary loss and fibrosis in SNx rats treated with chronic CXCR4 blockade. In contrast to the upregulation of CXCR4, SDF-1 transcript levels were decreased in SNx rat kidneys as well as in renal fibroblasts exposed to the pro-fibrotic cytokine transforming growth factor β (TGF-β), the latter effect being attenuated by histone deacetylase inhibition. Increased renal SDF-1 expression was, however, observed following the treatment of SNx rats with the ACE inhibitor, perindopril. Collectively, these observations indicate that local SDF-1/CXCR4 signaling functions to preserve microvascular integrity and prevent renal fibrosis. Augmentation of this pathway, either purposefully or serendipitously with either novel or existing therapies, may attenuate renal decline in CKD. |
| first_indexed | 2024-12-20T07:11:24Z |
| format | Article |
| id | doaj.art-512a27c8bad64906a8763177ff40c448 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T07:11:24Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-512a27c8bad64906a8763177ff40c4482022-12-21T19:48:53ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0193e9222710.1371/journal.pone.0092227SDF-1/CXCR4 signaling preserves microvascular integrity and renal function in chronic kidney disease.Li-Hao ChenSuzanne L AdvaniKerri ThaiM Golam KabirManish M SoodIan W GibsonDarren A YuenKim A ConnellyPhilip A MarsdenDarren J KellyRichard E GilbertAndrew AdvaniThe progressive decline of renal function in chronic kidney disease (CKD) is characterized by both disruption of the microvascular architecture and the accumulation of fibrotic matrix. One angiogenic pathway recently identified as playing an essential role in renal vascular development is the stromal cell-derived factor-1α (SDF-1)/CXCR4 pathway. Because similar developmental processes may be recapitulated in the disease setting, we hypothesized that the SDF-1/CXCR4 system would regulate microvascular health in CKD. Expression of CXCR4 was observed to be increased in the kidneys of subtotally nephrectomized (SNx) rats and in biopsies from patients with secondary focal segmental glomerulosclerosis (FSGS), a rodent model and human correlate both characterized by aberration of the renal microvessels. A reno-protective role for local SDF-1/CXCR4 signaling was indicated by i) CXCR4-dependent glomerular eNOS activation following acute SDF-1 administration; and ii) acceleration of renal function decline, capillary loss and fibrosis in SNx rats treated with chronic CXCR4 blockade. In contrast to the upregulation of CXCR4, SDF-1 transcript levels were decreased in SNx rat kidneys as well as in renal fibroblasts exposed to the pro-fibrotic cytokine transforming growth factor β (TGF-β), the latter effect being attenuated by histone deacetylase inhibition. Increased renal SDF-1 expression was, however, observed following the treatment of SNx rats with the ACE inhibitor, perindopril. Collectively, these observations indicate that local SDF-1/CXCR4 signaling functions to preserve microvascular integrity and prevent renal fibrosis. Augmentation of this pathway, either purposefully or serendipitously with either novel or existing therapies, may attenuate renal decline in CKD.http://europepmc.org/articles/PMC3956917?pdf=render |
| spellingShingle | Li-Hao Chen Suzanne L Advani Kerri Thai M Golam Kabir Manish M Sood Ian W Gibson Darren A Yuen Kim A Connelly Philip A Marsden Darren J Kelly Richard E Gilbert Andrew Advani SDF-1/CXCR4 signaling preserves microvascular integrity and renal function in chronic kidney disease. PLoS ONE |
| title | SDF-1/CXCR4 signaling preserves microvascular integrity and renal function in chronic kidney disease. |
| title_full | SDF-1/CXCR4 signaling preserves microvascular integrity and renal function in chronic kidney disease. |
| title_fullStr | SDF-1/CXCR4 signaling preserves microvascular integrity and renal function in chronic kidney disease. |
| title_full_unstemmed | SDF-1/CXCR4 signaling preserves microvascular integrity and renal function in chronic kidney disease. |
| title_short | SDF-1/CXCR4 signaling preserves microvascular integrity and renal function in chronic kidney disease. |
| title_sort | sdf 1 cxcr4 signaling preserves microvascular integrity and renal function in chronic kidney disease |
| url | http://europepmc.org/articles/PMC3956917?pdf=render |
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