Blockade of p38 Mitogen-Activated Protein Kinase and TGF-β1/Smad Signaling Pathways Rescues Bone Marrow–Derived Peritubular Capillary Endothelial Cells in Adriamycin-Induced Nephrosis
| Autor: | Sharon D. Ricardo, Jinhua Li, John F. Bertram, James A. Deane, Naomi Vittoria Campanale |
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| Rok vydání: | 2006 |
| Předmět: |
Male
CD31 MAPK/ERK pathway medicine.medical_specialty endocrine system diseases medicine.medical_treatment Apoptosis Bone Marrow Cells Smad Proteins SMAD Biology Kidney p38 Mitogen-Activated Protein Kinases Nephropathy Transforming Growth Factor beta1 Mice Internal medicine medicine Animals Mice Inbred BALB C Growth factor Endothelial Cells General Medicine medicine.disease Enzyme Activation Endothelial stem cell medicine.anatomical_structure Endocrinology Cytokine Doxorubicin Nephrology Cancer research Nephrosis Endothelium Vascular Signal Transduction |
| Zdroj: | Journal of the American Society of Nephrology. 17:2799-2811 |
| ISSN: | 1046-6673 |
| DOI: | 10.1681/asn.2006020130 |
| Popis: | The peritubular capillary (PTC) network is a component of the tubulointerstitium of the kidney with important roles in renal function and hemodynamics. Bone marrow (BM)-derived cells can contribute to repair of the renal PTC network after ischemic injury. However, the cell fate and the regulation of renal BM-derived cell engraftment in comparison with somatic cells during disease progression are unclear. This study characterized the time course and regulation of PTC endothelial cell injury in adriamycin (ADR)-induced nephropathy in mice, a model of chronic, irreversible, progressive renal disease. Enhanced green fluorescence protein-positive BM cells that coexpressed two endothelial cell markers, von Willebrand factor and CD31, were found to engraft into the PTC of chimeric ADR-injected mice in a time-dependent manner. The number of BM-derived PTC endothelial cells peaked 2 wk after ADR injection, then declined dramatically thereafter. In these mice, apoptosis was evident in BM-derived PTC endothelial cells, and the p38 mitogen-activated protein kinase (MAPK) and TGF-beta1/Smad signaling pathways were activated. Blocking both the p38 MAPK and TGF-beta1/Smad signaling pathways by administration of a p38 MAPK inhibitor (SB203580) and a TGF-beta receptor 1 inhibitor (ALK5I) to ADR-injected mice rescued BM-derived PTC endothelial cells from apoptosis, reduced the loss of PTC, and restored kidney function. Investigation into the signaling pathways that regulate the differentiation and survival of BM-derived cells that engraft into the kidney in the proinflammatory setting of progressive renal disease is vital for the successful development of cell-based therapies to promote renal regeneration and repair. |
| Databáze: | OpenAIRE |
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