Bacterial infection-mediated mucosal signalling induces local renal ischaemia as a defence against sepsis

Abstract

SummaryAscending urinary tract infections can cause extensive damage to kidney structure and function. We have used a number of advanced techniques including multiphoton microscopy to investigate the crucial early phases of uropathogenic Escherichia coli induced pyelonephritis within a living animal. Our results reveal a previously undescribed innate vascular response to mucosal infection, allowing isolation and eradication of the pathogen. The extremely rapid host response to mucosal infection was highlighted by the triggering of a cascade of events within 3-4 h. Epithelial signalling produced an increase in cellular O 2 consumption and affected microvascular flow by clotting, causing localized ischaemia. Subsequent ischaemic damage affected pathophysiology with actin re-arrangement and epithelial sloughing leading to paracellular bacterial movement. A denuded tubular basement membrane is shown to hinder immediate dissemination of bacteria, giving the host time to isolate the infection by clotting. Suppression of clotting by heparin treatment caused fatal urosepsis. Clinically these findings may be relevant in antibiotics delivery in pyelonephritis patients and to the use of anticoagulants in sepsis.

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

“…The same E. coli strain, missing only one virulence factor, required a far greater time to initiate this protective process. Tissue concentrations of cytokines were markedly elevated in the affected area, but were undetectable adjacent to the injected areas (66). Finally, prevention of this microvascular response resulted in widespread organ dissemination of the injected E. coli and death of the rat within 24 hours, which was not observed with the intact system (66).…”

“…A series of elegant studies directly demonstrated this phenomenon using fluorescent cytopathologic E. coli that were microinjected into early PT segments, with cellular and physiologic responses recorded using two-photon microscopy (64)(65)(66). Attachment to the apical membrane, but without penetration into or through the PTC monolayer barrier, resulted in rapid and selective termination of blood flow to the adjacent area, leading to vascular isolation of the infected area with localized hypoxia, wbc migration/infiltration, and necrosis.…”

The Proximal Tubule and Albuminuria

“…60 Albumin uptake by nonselective fluidphase endocytosis is probably a quantitatively important process in PTCs, as shown by the rapid cellular uptake of molecules not having receptors on the apical membrane, such as neutral fluorescent dextrans (markers of fluid-phase endocytosis). 61,62 The endocytic apparatus is found throughout the PT, although clathrincoated pits and vesicles are notably fewer in the S3 segment. 63 Expectedly, protein reabsorption and degradation are greatest in the S1 segment of the PTCs and least in the S3 segment.…”

Renal Hemodynamics in AKI

“…This reasoning is supported by observations derived from models of singlenephron tubular obstruction 48 and localized microinjection of Escherichia coli into early proximal tubule lumens. [49][50][51] Therefore, there seems to be a bidirectional and possibly synergistic crosstalk within the complex tubule-capillary microenvironment, with the sequence of events depending on the nature of insult. 23 Although microcirculatory changes may lead to tubular injury, the reverse may also be true.…”