Abstract
BackgroundDamage to the endothelium due to ischemia reperfusion injury (IRI) leads to a disruption of the microvasculature, which could be influenced by angiopoietin 1 via its effects on endothelium. We investigated the physiological and therapeutic roles of angiopoietin 1 in renal IRI using angiopoietin 1 knockout and over-expression mice.MethodsRenal IRI was induced by clamping the right renal artery seven days after left uninephrectomy for 25 min followed by reperfusion. A whole body angiopoietin 1 knockout was achieved by induction with tamoxifen. The renal tubule over-expression of angiopoietin 1 was induced by doxycycline.ResultsIn the normal mice, the renal expression of angiopoietin 1 increased 7 days to 14 days after IRI. The angiopoietin 1 knockout caused a delay in the recovery of renal function, less tubular regeneration and more residual tubular necrosis. The endothelial density was lower and the VE-cadherin protein loss was greater in the knockout mice. The over-expression of angiopoietin 1 attenuated the tubular necrosis and renal function impairment 1 and 3 days after IRI. The loss of the endothelium was ameliorated in the over-expression mice. This protective effect was associated with the up-regulation of the gene expression of epidermal growth factor, hepatocyte growth factor, and insulin like growth factor-1 and less tubular apoptosis. The over-expression of angiopoietin 1 stimulated tumor necrosis factor-α, C-C chemokine receptor type 2 and CX3C chemokine receptor 1 inflammatory gene expression, but did not influence macrophage infiltration.ConclusionsAltogether, the augmentation and downregulation of angiopoietin 1 attenuated renal damage and impaired renal recovery, respectively, by influencing the survival/regeneration of the endothelium. The manipulation of angiopoietin 1 represents a novel therapeutic approach for the treatment of ischemic kidney injury.
Highlights
Damage to the endothelium due to ischemia reperfusion injury (IRI) leads to a disruption of the microvasculature, which could be influenced by angiopoietin 1 via its effects on endothelium
Angiopoietin 1 (Angpt1) deficiency impaired the renal recovery after IRI Neoangiogenesis is an important repair process after renal IRI
To determine whether the up-regulation of Angpt1 plays a physiological role after renal IRI, we generated inducible whole-body Angpt1 knockout mice
Summary
Damage to the endothelium due to ischemia reperfusion injury (IRI) leads to a disruption of the microvasculature, which could be influenced by angiopoietin 1 via its effects on endothelium. A full recovery of renal microvascular blood flow after acute ischemia occurs in only one-third to one-quarter of cases (Conger et al, 1995). Damage to renal vascular endothelial cells plays a key role in the continued ischemia of the renal tubular epithelium and inflammatory response observed during ischemic AKI (Sutton et al, 2002). Increased renal peritubular capillary permeability was found to be a consequence of ischemic AKI in animal models (Sutton et al, 2003; Olof et al, 1990) These events lead to fluid leakage into the pericapillary space resulting in the formation of interstitial edema and reduction of renal blood flow. Increasing renal blood flow and protecting the endothelium from damage may attenuate ischemic reperfusion renal injury. The administration of differentiated endothelial cells has been shown to ameliorate the no-reflow phenomenon in the post-ischemic kidney and result in significant functional protection in IRI (Brodsky et al, 2002)
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