Fig. 1.

Inflammatory response and microcirculatory dysfunction. Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) are inflammatory mediators derived from bacteria and host immune cells, respectively. These inflammatory mediators bind to pattern recognition receptors (PRRs) expressed on the surface of innate immune cells, endothelial cells, and renal TECs initiating a downstream cascade of signals. This cascade increases the synthesis of proinflammatory cytokines, reactive oxygen species (ROS), oxidative stress, and endothelial activation by nitric oxide and nitric oxide synthase (iNOS) upregulation. During inflammation, DAMPs and PAMPs are filtered in the glomeruli. Once in the tubule, these bind the Toll-like receptor (TLRs) present in the apical membrane of the TEC. In addition, some evidence suggests that TECs are also exposed to the inflammatory mediators present in the peritubular circulation, creating a double-hit effect. Moreover, the inflammatory response can also injure the TECs by increasing the oxidative stress and producing ROS. Microcirculatory dysfunction is the result of a series of events that lead to an impaired delivery of oxygen and nutrients to the tissue. Endothelial activation provoked by the inflammatory response results in a cascade of events that lead to shedding of the glycocalyx, increased leukocyte migration, and endothelial permeability. In addition, microcirculatory dysfunction is characterized by a heterogeneous flow, reduced number of capillaries with continuous flow, with an associated increase of capillaries with sluggish or no flow. Sluggish and no flow, a result of the increased expression of adhesion molecules on the inflammatory and endothelial cells, facilitate the migration of neutrophils and macrophage to the interstitial space. Furthermore, the areas with sluggish flow have increased production of ROS and oxidative stress, manifested by TEC apical vacuolization.16,35,49 APC, antigen-presenting cell; RBC, red blood cell. (Adapted from: Peerapornratana, S., Manrique-Caballero, C. L., Gó mez, H. & Kellum, J. A. Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment.

Kidney international 96, 1083–1099, https://doi.org/10.1016/j.kint.2019.05.026 (2019).)