Search

Recent evidence suggests that bone marrow (BM)-derived cells may integrate into the kidney, giving rise to functional renal cell types, including endothelial and epithelial cells and myofibroblasts. BM-derived cells can contribute to repair of the renal peritubular capillary (PTC) network following acute ischemic injury. However, the cell fate and regulation of BM-derived cells during the progression of chronic renal disease remains unclear. Using chimeric mice transplanted with enhanced green fluorescent protein (EGFP)-expressing BM, we demonstrate that the number of BM-derived myofibroblasts coincided with the development of fibrosis in a mouse adriamycin (ADR)-induced nephrosis model of chronic, progressive renal fibrosis. Four weeks after ADR injection, increased numbers of BM-derived myofibroblasts were observed in the interstitium of ADR-injected mice. Six weeks after ADR injection, more than 30% of renal α-smooth muscle actin (+) (α-SMA+) interstitial myofibroblasts were derived from the BM. In addition, BM-derived cells were observed to express the endothelial cell marker CD31 and the myofibroblast marker α-SMA. Blockade of p38 mitogen-activated protein kinase (MAPK) and transforming growth factor (TGF)-β1/Smad2 signaling was found to protect BM-derived PTC endothelial cells and inhibit the number of BM-derived von Willebrand factor (vWF)(+)/EGFP(+)/α-SMA(+) cells, EGFP(+)/α-SMA(+) cells, and total α-SMA(+) cells in ADR-injected mice. Inhibition of the p38 MAPK and TGF-β1/Smad signaling pathways enhanced PTC repair by decreasing endothelial-myofibroblast transformation, leading to structural and functional renal recovery and the attenuation of renal interstitial fibrosis. Investigation of the signaling pathways that regulate the differentiation and survival of BM-derived cells in a progressive disease setting is vital for the successful development of cell-based therapies for renal repair. [ABSTRACT FROM AUTHOR]

Inflammation and fibrogenesis are the two determinants of the progression of renal fibrosis, the common pathway leading to end-stage renal disease. The p38 mitogen-activated protein kinase (MAPK) and transforming growth factor (TGF)-beta1/Smad signaling pathways play critical roles in inflammation and fibrogenesis, respectively. The present study examined the beneficial renoprotective effect of combination therapy using the p38 MAPK pathway inhibitor (SB203580) and a TGF-beta receptor I (ALK5) inhibitor (ALK5I) in a mouse model of adriamycin (ADR) nephrosis. The p38 MAPK and TGF-beta1/Smad2 signaling pathways were activated in ADR-induced nephropathy in a sequential time course manner. Two weeks after ADR injection, the combined administration of SB203580 (1 mg/kg/24 hours) and ALK5I (1 mg/kg/24 hours) markedly reduced p38 MAPK and Smad2 activities. Moreover, the co-administration of SB203580 and ALK5I to ADR-injected mice resulted in a down-regulation of total and active TGF-beta1 production, reduced myofibroblast accumulation, and decreased expression of collagen type IV and fibronectin. In these mice, retardation in the development of glomerulosclerosis and interstitial fibrosis was observed. In conclusion, although p38 MAPK and TGF-beta1/Smad signaling pathways are distinct they coordinate the progression of renal fibrosis in ADR nephrosis. The co-administration of a p38 MAPK inhibitor and an ALK5 inhibitor may have potential applications in the treatment of renal fibrosis.

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.