Abstract
Microvascular endothelial cells in the kidney have been a neglected cell type in sepsis-induced acute kidney injury (sepsis-AKI) research; yet, they offer tremendous potential as pharmacological targets. As endothelial cells in distinct cortical microvascular segments are highly heterogeneous, this Review focuses on endothelial cells in their anatomical niche. In animal models of sepsis-AKI, reduced glomerular blood flow has been attributed to inhibition of endothelial nitric oxide synthase activation in arterioles and glomeruli, whereas decreased cortex peritubular capillary perfusion is associated with epithelial redox stress. Elevated systemic levels of vascular endothelial growth factor, reduced levels of circulating sphingosine 1-phosphate and loss of components of the glycocalyx from glomerular endothelial cells lead to increased microvascular permeability. Although coagulation disbalance occurs in all microvascular segments, the molecules involved differ between segments. Induction of the expression of adhesion molecules and leukocyte recruitment also occurs in a heterogeneous manner. Evidence of similar endothelial cell responses has been found in kidney and blood samples from patients with sepsis. Comprehensive studies are needed to investigate the relationships between segment-specific changes in the microvasculature and kidney function loss in sepsis-AKI. The application of omics technologies to kidney tissues from animals and patients will be key in identifying these relationships and in developing novel therapeutics for sepsis.
Key points
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Microvascular endothelial cells in arterioles, glomeruli, peritubular capillaries and postcapillary venules in the kidney cortex have an intrinsic molecular and phenotypic heterogeneity and respond to sepsis-induced acute kidney injury (sepsis-AKI) conditions in a segment-specific manner.
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Clinical data suggest endothelial engagement in sepsis-AKI, although the contribution of the renal microvasculature is not yet clear; changes in the levels of soluble markers in blood and urine represent endothelial responses that can originate from any organ involved in sepsis pathophysiology.
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Not all molecules that control microvascular permeability and leukocyte recruitment in organs other than the kidney have a similar role in sepsis-AKI; this heterogeneity prevents extrapolation of mechanisms reported in other organs to the kidney.
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As endothelial cells rapidly lose their behaviour in culture, molecular mechanisms or cell responses to sepsis-AKI conditions and pharmacological interventions that are identified in vitro must be validated in vivo.
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Analysis of post-mortem kidney samples from patients with sepsis-AKI as well as serial plasma and urine samples and clinical data are required to effectively translate findings from animal models to the human disease.
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Molecularly mapping endothelial responses in time in various organs will provide a rational basis for the selection of molecules that can potentially serve as (soluble) biomarkers of endothelial responses in sepsis-AKI following validation in clinical samples.
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G.M., J.G.Z. and M.v.M. researched the data and wrote the article. G.M., J.G.Z. and J.A.A.M.K. made substantial contributions to discussion of the content. All authors reviewed or edited the manuscript before submission.
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J.G.Z., M.v.M. and J.A.A.M.K. declare no competing interests. G.M. is co-founder and chief technology/science officer of Vivomicx, which provides tissue laser microdissection and omics analysis services.
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Glossary
- Immune paralysis
-
A state in which immune cells show reduced responses to stimuli. Immune paralysis can occur in response to an overload of antigen and results in susceptibility to secondary infection. The cause of immune paralysis in sepsis is not known.
- Vascular integrity
-
The homeostatic condition of blood vessels in which endothelial cells in their natural environment regulate tissue perfusion, anticoagulant–procoagulant balance, microvascular permeability and leukocyte recruitment for immune surveillance purposes.
- Perm-selective barrier
-
The barrier formed by the glomerular endothelial cells that restricts the passage of proteins but enables passage of small molecules and water.
- Dwell time
-
The time that leukocytes spend in a particular vascular segment in a tissue in vivo. Dwell time is assessed using intravital microscopy technology.
- Epigenetic mechanisms
-
Mechanisms of control of cellular phenotype that do not involve the sequence of DNA nucleotides. Epigenetic mechanisms include chemical modifications such as methylation of DNA and histones that affect the accessibility of the DNA for transcription.
- Kinases
-
Enzymes that phosphorylate target proteins in the signal transduction cascade, leading to activation of transcription factors and other molecular entities that can change the phenotype of a cell.
- Signal transduction
-
The molecular mechanisms that are used by cells to relay an external stimulus into the nucleus to enable the necessary genes to be transcribed to mount a response.
- Evans Blue Dye accumulation
-
An in vivo technique to assess organ microvascular permeability based on intravenous administration of this dye, which non-covalently associates with albumin.
- Weibel–Palade bodies
-
Storage granules for P-selectin, angiopoietin 2 and von Willebrand factor proteins that are specifically located in endothelial cells.
- Precision cut kidney slice (PCKS) technology
-
A technology that reproducibly cuts tissue slices of predetermined size from kidney biopsy samples or whole kidney tissues. This technique preserves tissue architecture and enables cellular responses to drugs and experimental conditions to be studied.
- Laser microdissection
-
A technique that combines regular microscopy with laser-based release of selected parts of a tissue section for further molecular analyses.
- Omics
-
The collective name for platform technologies that assess the molecular status of tissues and/or cells in an unbiased manner, that is, the analysis is not restricted to pre-selected molecules.
- Pharmacolomics
-
The study of drug effects on target cells and surrounding tissues using omics platform technologies.
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Molema, G., Zijlstra, J.G., van Meurs, M. et al. Renal microvascular endothelial cell responses in sepsis-induced acute kidney injury. Nat Rev Nephrol 18, 95–112 (2022). https://doi.org/10.1038/s41581-021-00489-1
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DOI: https://doi.org/10.1038/s41581-021-00489-1
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