The multifaceted role of the renal microvasculature during acute kidney injury

Abstract

Pediatric acute kidney injury (AKI) represents a complex disease process for clinicians as it is multifactorial in cause and only limited treatment or preventatives are available. The renal microvasculature has recently been implicated in AKI as a strong therapeutic candidate involved in both injury and recovery. Significant progress has been made in the ability to study the renal microvasculature following ischemic AKI and its role in repair. Advances have also been made in elucidating cell-cell interactions and the molecular mechanisms involved in these interactions. The ability of the kidney to repair post AKI is closely linked to alterations in hypoxia, and these studies are elucidated in this review. Injury to the microvasculature following AKI plays an integral role in mediating the inflammatory response, thereby complicating potential therapeutics. However, recent work with experimental animal models suggests that the endothelium and its cellular and molecular interactions are attractive targets to prevent injury or hasten repair following AKI. Here, we review the cellular and molecular mechanisms of the renal endothelium in AKI, as well as repair and recovery, and potential therapeutics to prevent or ameliorate injury and hasten repair.

Keywords: Acute kidney injury; Endothelium; Immune response; Ischemia reperfusion injury; Microvasculature; Tissue hypoxia.

Fig. 1

Injury, repair, and resolution during ischemic acute kidney injury (AKI). Following ischemia, there is substantial microvascular injury, leading to increased coagulation, reduced nitric oxide release, macrophage recruitment, and increased hypoxia. These events in turn lead to significant tubular injury and death, ultimately causing a decrease in glomerular filtration rate (GFR). Following reperfusion, the kidney enters adaptive repair in which inflammation and debris begins to resolve through a switch from M1 macrophages to M2 macrophages. Both endothelial repair and epithelial tubular proliferation begin, leading to resolution. Adapted from Fernenback and Bonventre [121] with permission from Macmillan Publishers Ltd

Fig. 2

Hypoxic markers are present following ischemic reperfusion injury. a, b Hypoxyprobe- (red) and endomucin- (green) stained kidneys 1 day following 20 min of unilateral ischemic reperfusion injury (IR) (b), and the contralateral controls (a). One day following injury, ischemic kidneys (b) display markedly more hypoxic tubules (arrows) when compared with the contralateral control (a). Scale bars:100 μm