Renal endothelial dysfunction in acute kidney ischemia reperfusion injury

Abstract

Acute kidney injury is associated with alterations in vascular tone that contribute to an overall reduction in GFR. Studies in animal models indicate that ischemia triggers alterations in endothelial function that contribute significantly to the overall degree and severity of a kidney injury. Putative mediators of vasoconstriction that may contribute to the initial loss of renal blood flow and GFR are highlighted. In addition, there is discussion of how intrinsic damage to the endothelium impairs homeostatic responses in vascular tone as well as promotes leukocyte adhesion and exacerbating the reduction in renal blood flow. The timing of potential therapies in animal models as they relate to the evolution of AKI, as well as the limitations of such approaches in the clinical setting are discussed. Finally, we discuss how acute kidney injury induces permanent alterations in renal vascular structure. We posit that the cause of the sustained impairment in kidney capillary density results from impaired endothelial growth responses and suggest that this limitation is a primary contributing feature underlying progression of chronic kidney disease.

Figure 1

Summary of tubular and vascular events in the initiation and recovery from ischemic AKI. Top Panel, Time line of loss of GFR in response to renal ischemia shown in relation to the corresponding phases (Initiation, Extension, Maintenance, and Recovery) described by Molitoris and Sutton [37]. Early reduction of GFR in the initiation phase is mediated initially be changes in vascular tone. Arrows and lines show the anticipated effects of endothelial targeted treatments. Treatment A1 (purple dashed line) indicates preservation of function when treatments effecting tone, (e.g., supplementation of NO or vasoconstrictor antagonists) are provided during initiation, while Treatment A2 (purple dotted line) shows a lack of efficacy of these treatments when provided during the extension phase. Similarly, treatments that disrupt endothelial leukocyte interactions are effective when provided during initiation (B1, green dashed line). The effect of anti-leukocyte during the extension phase is not yet clear, but is predicted to have potential beneficial effects (B2?, green dotted line). Capillary density is indicated by the red lines: rarefaction progresses in the extension and maintenance phases and does not resolve; pro-vasculogenic treatments preserve capillary density when provided during the extension phase (C1), but lack effect at later times (C2). Bottom Panel summarizes altered cellular and molecular events associated with the phases of injury in both the tubular and vascular compartments, with an emphasis on events linked with vascular perfusion. The photomicrograph in “normal” state illustrates intact vascular density in control rats, while capillary rarefaction is observed in the post-recovery phase (photomicrographs from [112]). Loss of microvasculature occurs, in part, via endothelial mesenchymal transition (EndoMT) which can be observed in the extension and maintenance phase. EndoMT is illustrated by co-localizing S100-A4 (red) in capillary EC (blue) (highlighted by thin black arrow, from citation [122].

Figure 1

Summary of tubular and vascular events in the initiation and recovery from ischemic AKI. Top Panel, Time line of loss of GFR in response to renal ischemia shown in relation to the corresponding phases (Initiation, Extension, Maintenance, and Recovery) described by Molitoris and Sutton [37]. Early reduction of GFR in the initiation phase is mediated initially be changes in vascular tone. Arrows and lines show the anticipated effects of endothelial targeted treatments. Treatment A1 (purple dashed line) indicates preservation of function when treatments effecting tone, (e.g., supplementation of NO or vasoconstrictor antagonists) are provided during initiation, while Treatment A2 (purple dotted line) shows a lack of efficacy of these treatments when provided during the extension phase. Similarly, treatments that disrupt endothelial leukocyte interactions are effective when provided during initiation (B1, green dashed line). The effect of anti-leukocyte during the extension phase is not yet clear, but is predicted to have potential beneficial effects (B2?, green dotted line). Capillary density is indicated by the red lines: rarefaction progresses in the extension and maintenance phases and does not resolve; pro-vasculogenic treatments preserve capillary density when provided during the extension phase (C1), but lack effect at later times (C2). Bottom Panel summarizes altered cellular and molecular events associated with the phases of injury in both the tubular and vascular compartments, with an emphasis on events linked with vascular perfusion. The photomicrograph in “normal” state illustrates intact vascular density in control rats, while capillary rarefaction is observed in the post-recovery phase (photomicrographs from [112]). Loss of microvasculature occurs, in part, via endothelial mesenchymal transition (EndoMT) which can be observed in the extension and maintenance phase. EndoMT is illustrated by co-localizing S100-A4 (red) in capillary EC (blue) (highlighted by thin black arrow, from citation [122].