Renal tubular atrophy accompanies many proteinuric renal diseases, suggesting that glomerular proteinuria injures the tubules. However, local or systemic inflammation and filtration of abnormal proteins known to directly injure tubules are also present in many of these diseases and animal models; therefore, whether glomerular proteinuria directly causes tubular injury is unknown. Here, we examined the renal response to proteinuria induced by selective podocyte loss. We generated mice that express the diphtheria toxin receptor exclusively in podocytes, allowing reproducible dose-dependent, specific ablation of podocytes by administering diphtheria toxin. Ablation of ,20% of podocytes resulted in profound albuminuria that resolved over 1-2 weeks after the re-establishment of normal podocyte morphology. Immediately after the onset of albuminuria, proximal tubule cells underwent a transient burst of proliferation without evidence of tubular damage or increased apoptosis, resulting in an increase in total tubular cell numbers. The proliferative response coincided with detection of the growth factor Gas6 in the urine and phosphorylation of the Gas6 receptor Axl in the apical membrane of renal tubular cells. In contrast, ablation of .40% of podocytes led to progressive glomerulosclerosis, profound tubular injury, and renal failure. These data suggest that glomerular proteinuria in the absence of severe structural glomerular injury activates tubular proliferation, potentially as an adaptive response to minimize the loss of filtered proteins.

Recent studies have demonstrated that erythropoietin (EPO) receptors are expressed on tubular epithelial cells and that EPO can protect tubular cells from injury in vitro and in vivo. Separate studies have demonstrated that marrow stromal cells (MSCs) exert a renoprotective effect in ischemia-reperfusion and cisplatin tubular injury via the secretion of factors that reduce apoptosis and increase proliferation of tubular epithelial cells. In the present study we demonstrate that MSCs express EPO receptors and that EPO can protect MSCs from serum deprivation-induced cell death and can stimulate MSC proliferation in vitro. The administration of EPO to mice resulted in the expansion of CD45-Flk1-CD105+ MSCs in the bone marrow and in the spleen and mobilized these cells as well as CD45-Flk1+ endothelial progenitor cells into the peripheral circulation. Consistent with previous reports, the administration of EPO diminished the decline in renal function associated with cisplatin administration. This effect was partially reproduced by intraperitoneal injection of cultured EPO-mobilized cells in cisplatin-treated mice. Thus the in vivo expansion and/or activation of these cells may contribute to the renoprotective effects of EPO to protect tubular cells from toxic injury.

ABSTRACT. To explore the mechanism whereby stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) jointly mobilize bone marrow stem cells (BMSCs) and promote kidney repair, male Sprague-Dawley rats were randomly assigned into 4 groups. In the treatment control group, rats were administered SCF (200 μg· kg