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bioRxiv · 10.1101/2022.06.21.496998

Inflammatory mediators act at renal pericytes to elicit contraction of vasa recta and reduce pericyte density along this medullary vascular network

Lilley, R. J.·Taylor, K.·Wildman, S. S. P.·Peppiatt-Wildman, C. M.
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Abstract

Regardless of initiating cause, renal injury promotes a potent pro-inflammatory environment in the outer medulla and a concomitant sustained decrease in medullary blood flow (MBF). This decline in MBF is believed to one of the critical events in the pathogenesis of acute kidney injury (AKI), yet the precise cellular mechanism underlying this are still to be fully elucidated. MBF is regulated by contractile pericyte cells that reside on the descending vasa recta (DVR) capillaries, which are the primary source of blood flow to the medulla. Using the rodent and murine live kidney slice models, we sought to investigate the acute effects of key medullary inflammatory mediators TNF-, IL-1{beta}, IL-33, IL-18, C3a and C5a on vasa recta pericytes. Live kidney slices taken from both mice and rats and exposed to TNF-, IL-18, IL-33, and C5a demonstrated a real-time pericyte-mediated constriction of DVR. When pro-inflammatory mediators were applied in the presence of the AT1-R blocker Losartan the inflammatory-mediated constriction that had previously been observed was significantly attenuated. When live kidney slices were exposed to inflammatory mediators for 4-hours, we noted a significantly reduction in the number of NG2+ positive pericytes along vasa recta capillaries in both rodent and murine kidney slices. Data collected in this study, demonstrate that inflammatory mediators can dysregulate pericytes to constrict DVR diameter and reduce the density of pericytes along vasa recta vessels, further diminishing the regulatory capacity of the capillary network. We postulate that preliminary findings here suggest pericytes play a role in AKI. New & NoteworthyHow medullary blood flow (MBF) becomes disproportionately dysregulated following renal injury is poorly understood yet is associated with worse prognostic outcomes following AKI. This study shows in both rats and mice that inflammatory mediators associated with AKI have acute and sustained microvascular actions at pericytes eliciting dysregulation of descending vasa recta (DVR) diameter and their loss from the DVR. This work highlights a possible pathology behind the dysregulation and reduction of MBF observed following AKI.

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Lilley, R. J., Taylor, K., Wildman, S. S. P., Peppiatt-Wildman, C. M.. 2022-06-21. Inflammatory mediators act at renal pericytes to elicit contraction of vasa recta and reduce pericyte density along this medullary vascular network. https://doi.org/10.1101/2022.06.21.496998

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