Therapeutic translation in acute kidney injury: the epithelial/endothelial axis

Inflammation in AKI

“…Multiple inflammatory and parenchymal cell types are involved in AKI, and in fact, an important epithelial-endothelial axis exists that promotes the infiltration of inflammatory cells after initial injury. 38 Because there are so many different cell types involved in the inflammatory response and because different inflammatory cells contribute to injury and repair, it is very important to be mindful of the phenotype and kinetics of the inflammatory response in designing effective anti-inflammatory approaches to AKI (Figure 2). …”

“…Injured parenchymal cells, such as renal tubular epithelial cells and endothelial cells, release damageassociated molecular patterns that trigger innate immune receptors on nearby healthy cells, thereby transducing death signals to the nearby healthy cells and propagating the local tissue injury. 38 Experimental data from many laboratories show that parenchymal cell injury can be ameliorated by blockade of membranebound or intracytoplasmic innate immune receptors. Rodent models show that these receptors are rapidly activated after renal artery occlusion, leading to a cascade of intracellular signaling events that ultimately cause apoptosis and necrosis of the triggered cells and the production of proinflammatory molecules.…”

“…6 Thus, there has been much interest in adhesion molecule blockade in AKI as a way to interrupt the epithelialendothelial axis of injury. 38,39 Molecules generated within injured cells have also been recently identified as potential targets to abrogate inflammation. 40 For example, the cysteine proteases (calpains and caspases) play a role in hypoxia-induced injury in proximal tubular cells, and mitochondrial mediators are gaining interest as potential antiinflammatory targets in several cell types.…”

Renal Hemodynamics in AKI

“…[20][21][22] Both ischemia and sepsis have profound effects on the integrity and function of peritubular capillaries. 23 Rodent models of ischemia-reperfusion show compromised peritubular perfusion characterized by sluggish and retrograde blood flow that develops within minutes after reperfusion 24,25 followed by restoration of normal flow within the first 4 hours, only to dramatically worsen over the next 20 hours. 21,26 Similarly, rodent models of acute endotoxemia suggest that cortical peritubular capillaries are among the first renal structures injured.…”

“…Further mechanisms include direct inflammatory injury of endothelial cells and activation of the epithelial-endothelial axis by inflammatory signals released from tubular cells exposed to toxicity of filtered danger signals. 23 As a result, the balance is strongly tipped toward increased microvascular permeability, endothelial cell inflammation, imbalance between vasodilating and vasoconstricting factors, and activation of coagulation. The intricate molecular pathways within the local microenvironment of endothelial cells fall outside the scope of this work, and the reader is referred to recent in-depth reviews.…”