Endothelial dysfunction in ischemic acute renal failure: rescue by transplanted endothelial cells

Abstract

There is accumulating circumstantial evidence suggesting that endothelial cell dysfunction contributes to the "no-reflow" phenomenon in postischemic kidneys. Here, we demonstrated the vulnerability of in vitro, ex vivo, and in vivo endothelial cells exposed to pathophysiologically relevant insults, such as oxidative and nitrosative stress or ischemia. All of these stimuli compromised the integrity of the endothelial lining. Next, we performed minimally invasive intravital microscopy of blood flow in peritubular capillaries, which provided direct evidence of the existence of the no-reflow phenomenon, attributable, at least in part, to endothelial injury. In an attempt to ameliorate the hemodynamic consequences of lost endothelial integrity, we transplanted endothelial cells or surrogate cells expressing endothelial nitric oxide synthase into rats subjected to renal artery clamping. Implantation of endothelial cells or their surrogates expressing functional endothelial nitric oxide synthase in the renal microvasculature resulted in a dramatic functional protection of ischemic kidneys. These observations strongly suggest that endothelial cell dysfunction is the primary cause of the no-reflow phenomenon, which, when ameliorated, results in prevention of renal injury seen in acute renal failure.

Cell death induced by acute renal injury: a perspective on the contributions of apoptosis and necrosis

“…The endothelial cells undergo swelling, leakage, cell activation, and dysfunction (111,158). Injection of endothelial cells expressing endothelial nitric oxide synthase into rats subjected to renal ischemia resulted in the implantation of these cells in the renal microvasculature and functional protection of ischemic kidneys (23). A recent study demonstrated that permanent damage to peritubular capillaries occurred in rats that underwent renal ischemia and may partly account for the pathogenesis of chronic renal failure in this setting (11).…”

“…The superoxides can react with nitric oxide (NO) and form peroxynitrate (53,69). ROS has been implicated in mediating ischemic renal injury, and treatment with antioxidants or free radical scavengers ameliorated renal injury (23,167,181). The mechanisms by which ROS induce damage to the cells include peroxidation of lipid membranes, protein denaturation, and DNA strand breaks (34).…”

Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation

“…Renal microcirculation is the first target of ischemia-reperfusion injury due to its high sensitivity to hypoxia and its proximity to the blood flow. Ischemia-reperfusion injury causes the phenotype of the vascular endothelial cells to switch from an anti-inflammatory/coagulant to a pro-inflammatory/coagulant [50] phenotype, combining self-antigen presentation [51], innate immune system activation [52], endothelial cell swelling, altered cell-cell contact and altered endothelial cell-basement membrane attachment [53][54][55]. These phenomena are associated with the no-reflow phenomenon characterized by an increase in the impedance of the microvascular blood flow after re-opening of occluded/ thrombosed vessels [56,57].…”

Preserving postischemic reperfusion in the kidney: a role for extracellular adenosine

“…The impaired postischemic reflow shown by Grenz et al (5) to be alleviated by Ent1-sensitive Adora2b activation is well established to play a major role in the injury caused in small animal ischemia/reperfusion models (22)(23)(24)(25). For technical reasons, Grenz et al measured capillary perfusion in the superficial cortex, but it is more severely impaired in the deep cortex and outer medulla, where most structural damage develops (22)(23)(24)(25).…”

“…For technical reasons, Grenz et al measured capillary perfusion in the superficial cortex, but it is more severely impaired in the deep cortex and outer medulla, where most structural damage develops (22)(23)(24)(25). The authors have done service to the field by placing the complexities of adenosine transport and signaling in the context of reperfusion abnormalities.…”