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.
The recent refinement and computerization of intravital microscopy have permitted us to monitor microcirculation in vivo with minimal invasion. Here, we report on the first findings made with the use of a pencil-lens intravital microscope as applied to the ischemic rat kidney. Peritubular capillary and glomerular blood flow were monitored under basal conditions, during renal artery occlusion, and immediately after release of the clamp. Erythrocyte velocity was calculated as an angle in consecutive spatiotemporal images. Intravital videomicroscopy during the reperfusion period showed intermittent cessation and partial recovery of blood flow in both peritubular and glomerular capillaries. Blood flow was uniformly orthograde under control conditions; however, the retrograde flow occurred on reperfusion. The patency of peritubular capillaries was partially compromised during the early reperfusion period but rapidly recovered. The recovery of glomerular microcirculation occurred faster than that of peritubular capillaries. We suggest that a functional vasculopathy develops very early in the course of ischemia-reperfusion in superficial cortical microvasculature and is more pronounced in peritubular capillaries, thus accounting for the development of patchy injury of tubular epithelia.
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