S. Our study further demonstrated that glomerular endothelial cell dysfunction preceded podocyte injury and that glomerular endothelial cells underwent apoptosis earlier than podocytes, further supporting the notion that besides podocytes, glomerular endothelial cells also play an important role in glomerulopathy. Earlier 
studies [43,44] have shown that mice with eNOS deficiency had significantly elevated blood pressures associated with increase in renin activities. In the present study, ADR treatment did not further alter the increased blood pressures compared with NS treatment in eNOS-deficient mice, suggesting that high blood pressure may contribute to the initiation of ADRinduced kidney injury but ADR-induced kidney damage per se did not have an impact on blood pressure. Podocytes and glomerular endothelial cells cross-talk through the secretion of cytokines and growth factors [45?8]. Sison et al [46] elegantly demonstrated through the use of genetically modified animals that vascular endothelial growth factor-A (VEGF-A) secreted by podocytes binds to VEGFR2 on adjacent endothelial cells to participate in kidney development and to maintain endothelial cell survival and function. Davis et al [47] demonstrated that podocyte-specific expression of angiopoietin-2 induced apoptosis of the glomerular endothelial cells and proteinuria but the podocytes and the GBM remained intact. Slater et al [48] demonstrated that co-culture of human glomerular endothelial cell under laminar shear stress with podocytes resulted in an increase in phosphorylation of Vasodilatorstimulated phosphoprotein at S157 and S239 in podocytes and a decrease in podocyte 3397-23-7 manufacturer barrier resistance. These results suggest that glomerular endothelial cells under stress may release mediators to cross-talk with podocytes thus influencing podocyte behaviour. In our study podocytes cultured with conditioned media from MMECs over-expressing eNOS were resistant to TNF-a-induced loss of synaptopodin, providing direct evidence that glomerular endothelial cells may protect podocytes from inflammatory insult through secreting mediators or change their production of a variety of cytokines, proteoglycans and growth factors. What mediators are 
released from endothelial cells and the exact mechanisms on how endothelial cells influence podocytes requires further investigation. The other cell type that needs to be considered in the glomerulus is the mesangial cell which expresses nitric oxide (NO) receptors [49]. Mesangial cells require NO to survive andGlomerular Endothelial Cell Injuryregulate their function [50,51]. In fact, eNOS deficiency also has an impact on mesangial cells, as evidenced by mesangiolysis [6?]. The interaction between glomerular endothelial cells and mesangial cells warrants further investigation. In conclusion, our study demonstrated that endothelial dysfunction and damage precedes podocyte injury in ADRinduced nephropathy. In addition, glomerular endothelial cells may protect podocytes through secreting mediators. Understanding the role of glomerular endothelial dysfunction in the pathogenesis of glomerular injury and sclerosis will greatly aid in the design of novel therapeutic approaches for slowing the KDM5A-IN-1 chemical information progressive of renal disease.AcknowledgmentsDr Jeffrey Kopp at Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda kindly provided us with a mouse podocyte cell line. Confocal imaging was perfo.S. Our study further demonstrated that glomerular endothelial cell dysfunction preceded podocyte injury and that glomerular endothelial cells underwent apoptosis earlier than podocytes, further supporting the notion that besides podocytes, glomerular endothelial cells also play an important role in glomerulopathy. Earlier studies [43,44] have shown that mice with eNOS deficiency had significantly elevated blood pressures associated with increase in renin activities. In the present study, ADR treatment did not further alter the increased blood pressures compared with NS treatment in eNOS-deficient mice, suggesting that high blood pressure may contribute to the initiation of ADRinduced kidney injury but ADR-induced kidney damage per se did not have an impact on blood pressure. Podocytes and glomerular endothelial cells cross-talk through the secretion of cytokines and growth factors [45?8]. Sison et al [46] elegantly demonstrated through the use of genetically modified animals that vascular endothelial growth factor-A (VEGF-A) secreted by podocytes binds to VEGFR2 on adjacent endothelial cells to participate in kidney development and to maintain endothelial cell survival and function. Davis et al [47] demonstrated that podocyte-specific expression of angiopoietin-2 induced apoptosis of the glomerular endothelial cells and proteinuria but the podocytes and the GBM remained intact. Slater et al [48] demonstrated that co-culture of human glomerular endothelial cell under laminar shear stress with podocytes resulted in an increase in phosphorylation of Vasodilatorstimulated phosphoprotein at S157 and S239 in podocytes and a decrease in podocyte barrier resistance. These results suggest that glomerular endothelial cells under stress may release mediators to cross-talk with podocytes thus influencing podocyte behaviour. In our study podocytes cultured with conditioned media from MMECs over-expressing eNOS were resistant to TNF-a-induced loss of synaptopodin, providing direct evidence that glomerular endothelial cells may protect podocytes from inflammatory insult through secreting mediators or change their production of a variety of cytokines, proteoglycans and growth factors. What mediators are released from endothelial cells and the exact mechanisms on how endothelial cells influence podocytes requires further investigation. The other cell type that needs to be considered in the glomerulus is the mesangial cell which expresses nitric oxide (NO) receptors [49]. Mesangial cells require NO to survive andGlomerular Endothelial Cell Injuryregulate their function [50,51]. In fact, eNOS deficiency also has an impact on mesangial cells, as evidenced by mesangiolysis [6?]. The interaction between glomerular endothelial cells and mesangial cells warrants further investigation. In conclusion, our study demonstrated that endothelial dysfunction and damage precedes podocyte injury in ADRinduced nephropathy. In addition, glomerular endothelial cells may protect podocytes through secreting mediators. Understanding the role of glomerular endothelial dysfunction in the pathogenesis of glomerular injury and sclerosis will greatly aid in the design of novel therapeutic approaches for slowing the progressive of renal disease.AcknowledgmentsDr Jeffrey Kopp at Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda kindly provided us with a mouse podocyte cell line. Confocal imaging was perfo.
