Role of fibrinogen in acute ischemic kidney injury

Sörensen-Zender, Inga; Rong, Song; Susnik, Nathan; Lange, J.; Gueler, Faikah; Degen, Jay L.; Melk, Anette; Haller, Hermann; Schmitt, Roland

doi:10.1152/ajprenal.00418.2012

Cited by 30 publications

(40 citation statements)

References 40 publications

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“…In the mouse model, the proinflammatory profile upon catheterization was dominated by the up-regulation of IL-6, which is involved in the induction of Fg expression and potentiation of its release into the bladder lumen (26,38,(50)(51)(52). Under normal circumstances, Fg is required to aid in the healing of damaged tissue (50,52).…”

Section: Discussionmentioning

confidence: 99%

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

Walker

Flores-Mireles

Pinkner

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

164

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Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging cause of catheter-associated urinary tract infection (CAUTI), which frequently progresses to more serious invasive infections. We adapted a mouse model of CAUTI to investigate how catheterization increases an individual's susceptibility to MRSA UTI. This analysis revealed that catheterization was required for MRSA to achieve high-level, persistent infection in the bladder. As shown previously, catheter placement induced an inflammatory response resulting in the release of the host protein fibrinogen (Fg), which coated the bladder and implant. Following infection, we showed that MRSA attached to the urothelium and implant in patterns that colocalized with deposited Fg. Furthermore, MRSA exacerbated the host inflammatory response to stimulate the additional release and accumulation of Fg in the urinary tract, which facilitated MRSA colonization. Consistent with this model, analysis of catheters from patients with S. aureus-positive cultures revealed colocalization of Fg, which was deposited on the catheter, with S. aureus. Clumping Factors A and B (ClfA and ClfB) have been shown to contribute to MRSA-Fg interactions in other models of disease. We found that mutants in clfA had significantly greater Fg-binding defects than mutants in clfB in several in vitro assays. Paradoxically, only the ClfB − strain was significantly attenuated in the CAUTI model. Together, these data suggest that catheterization alters the urinary tract environment to promote MRSA CAUTI pathogenesis by inducing the release of Fg, which the pathogen enhances to persist in the urinary tract despite the host's robust immune response.host-pathogen interactions | MRSA CAUTI | ClfB-fibrinogen interactions

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Section: Discussionmentioning

confidence: 99%

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

Walker

Flores-Mireles

Pinkner

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

164

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“…Recent studies correlated Lcn2 and Fg-b expression with AKI development in mice. 28,29 Overexpression of these markers of renal injury was reduced by wild-type MSCs and EVs but not MSC-Dsh and EV-Dsh. Inefficiency of Drosha-knockdown cells and EVs in inducing renal repair was observed at not only morphologic level but also, functional levels as indicated by the persistence of elevated BUN levels.…”

Section: Discussionmentioning

confidence: 99%

“…These data collectively indicated that injured renal tubules can initiate local Fg synthesis. 29 Immunohistochemistry analysis of Fg-b in untreated AKI mice showed a strong peritubular staining for Fg and some positivity in the tubular cell cytoplasm ( Figure 7F). Tubular staining was not observed in kidneys from healthy mice and was markedly reduced in mice treated with MSC-CTRL and EV-CTRL but not MSC-Dsh and EV-Dsh ( Figure 7F).…”

Section: Effect Of Drosha Knockdown On the Expression Of Markers Of Kmentioning

confidence: 96%

“…Kidneys from untreated AKI mice showed elevated levels of transcripts coding for markers of tubular damage, such as lipocalin 2 (Lcn2) 28 and fibrinogen (Fg) subunits, 29 as detected by RNA-Seq analysis. In healthy mice, no expression of Lcn2 was observed.…”

Section: Effect Of Drosha Knockdown On the Expression Of Markers Of Kmentioning

confidence: 97%

“…29 AKI induced the upregulation of all of the Fg subunits (subunits-a, -b, and -g) ( Figure 7C). MSC-CTRL-or EV-CTRL-treated mice showed significant downregulation of Fg-b and less relevant reductions of a-and g-subunits.…”

Section: Effect Of Drosha Knockdown On the Expression Of Markers Of Kmentioning

confidence: 98%

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AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs

Collino

Bruno²,

Incarnato

et al. 2015

Journal of the American Society of Nephrology

216

227

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Phenotypic changes induced by extracellular vesicles have been implicated in mesenchymal stromal cellpromoted recovery of AKI. MicroRNAs are potential candidates for cell reprogramming toward a proregenerative phenotype. The aim of this study was to evaluate whether microRNA deregulation inhibits the regenerative potential of mesenchymal stromal cells and derived extracellular vesicles in a model of glycerol-induced AKI in severe combined immunodeficient mice. We generated mesenchymal stromal cells depleted of Drosha to alter microRNA expression. Drosha-knockdown cells produced extracellular vesicles that did not differ from those of wild-type cells in quantity, surface molecule expression, and internalization within renal tubular epithelial cells. However, these vesicles showed global downregulation of microRNAs. Whereas wild-type mesenchymal stromal cells and derived vesicles administered intravenously induced morphologic and functional recovery in AKI, the Drosha-knockdown counterparts were ineffective. RNA sequencing analysis showed that kidney genes deregulated after injury were restored by treatment with mesenchymal stromal cells and derived vesicles but not with Drosha-knockdown cells and vesicles. Gene ontology analysis showed in AKI an association of downregulated genes with fatty acid metabolism and upregulated genes with inflammation, matrix-receptor interaction, and cell adhesion molecules. These alterations reverted after treatment with wild-type mesenchymal stromal cells and extracellular vesicles but not after treatment with the Drosha-knockdown counterparts. In conclusion, microRNA depletion in mesenchymal stromal cells and extracellular vesicles significantly reduced their intrinsic regenerative potential in AKI, suggesting a critical role of microRNAs in recovery after AKI.

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Pathophysiology of Red Blood Cell Trapping in Ischemic Acute Kidney Injury

McLarnon

2023

Comprehensive Physiology

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Red blood cell (RBC) trapping describes the accumulation of RBCs in the microvasculature of the kidney outer medulla that occurs following ischemic acute kidney injury (AKI). Despite its prominence in human kidneys following AKI, as well as evidence from experimental models demonstrating that the severity of RBC trapping is directly correlated with renal recovery, to date, RBC trapping has not been a primary focus in understanding the pathogenesis of ischemic kidney injury. New evidence from rodent models suggests that RBC trapping is responsible for much of the tubular injury occurring in the initial hours after kidney reperfusion from ischemia. This early injury appears to result from RBC cytotoxicity and closely reflects the injury profile observed in human kidneys, including sloughing of the medullary tubules and the formation of heme casts in the distal tubules. In this review, we discuss what is currently known about RBC trapping. We conclude that RBC trapping is likely avoidable. The primary causes of RBC trapping are thought to include rheologic alterations, blood coagulation, tubular cell swelling, and increased vascular permeability; however, new data indicate that a mismatch in blood flow between the cortex and medulla where medullary perfusion is maintained during cortical ischemia is also likely critical. The mechanism(s) by which RBC trapping contributes to renal functional decline require more investigation. We propose a renewed focus on the mechanisms mediating RBC trapping, and RBC trapping‐associated injury is likely to provide important knowledge for improving AKI outcomes. © 2024 American Physiological Society. Compr Physiol 14:5325‐5343, 2024.

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Role of fibrinogen in acute ischemic kidney injury

Cited by 30 publications

References 40 publications

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs

Pathophysiology of Red Blood Cell Trapping in Ischemic Acute Kidney Injury

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