Blockade of p38 mitogen-activated protein kinase and TGF-beta1/Smad signaling pathways rescues bone marrow-derived peritubular capillary endothelial cells in adriamycin-induced nephrosis.
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.
Li
Jinhua
J
Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Victoria 3800, Australia.
Deane
James A
JA
Campanale
Naomi V
NV
Bertram
John F
JF
Ricardo
Sharon D
SD
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000502:physiology*; D004317:Doxorubicin / Q000633:toxicity*; D042783:Endothelial Cells; D004730:Endothelium, Vascular / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D007668:Kidney / Q000166:cytology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009401:Nephrosis / Q000139:chemically induced / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D004317:Doxorubicin; D048051:p38 Mitogen-Activated Protein Kinases