Endothelium structure and function in kidney health and disease

Abstract

The kidney harbours different types of endothelia, each with specific structural and functional characteristics. The glomerular endothelium, which is highly fenestrated and covered by a rich glycocalyx, participates in the sieving properties of the glomerular filtration barrier and in the maintenance of podocyte structure. The microvascular endothelium in peritubular capillaries, which is also fenestrated, transports reabsorbed components and participates in epithelial cell function. The endothelium of large and small vessels supports the renal vasculature. These renal endothelia are protected by regulators of thrombosis, inflammation and complement, but endothelial injury (for example, induced by toxins, antibodies, immune cells or inflammatory cytokines) or defects in factors that provide endothelial protection (for example, regulators of complement or angiogenesis) can lead to acute or chronic renal injury. Moreover, renal endothelial cells can transition towards a mesenchymal phenotype, favouring renal fibrosis and the development of chronic kidney disease. Thus, the renal endothelium is both a target and a driver of kidney and systemic cardiovascular complications. Emerging therapeutic strategies that target the renal endothelium may lead to improved outcomes for both rare and common renal diseases.

Key points

  • The kidney contains diverse populations of endothelial cells, including the glomerular endothelium, microvascular endothelium in peritubular capillaries and the endothelium of large and small vessels, and each of these populations has specific characteristics and functions.

  • Homeostasis of renal endothelial cells is crucial for the preservation of glomerular structure and function, the preservation of an anti-inflammatory and an antithrombotic environment and the prevention of renal fibrosis.

  • Glomerular endothelial cells, in particular, are susceptible to injury in typical and atypical haemolytic uraemic syndrome, lupus nephritis, antineutrophil cytoplasmic antibody vasculitides and antibody-mediated rejection as well as in situations of vascular endothelial growth factor (VEGF) depletion.

  • Common forms of chronic kidney disease (CKD) — diabetic kidney disease and arteriolar nephrosclerosis — are also characterized by renal endothelial dysfunction.

  • Alterations in endothelial repair capacity, endothelial-to-mesenchymal transition and capillary rarefaction contribute to the fibrogenic processes that lead to CKD.

  • Therapeutic strategies aimed at preserving and/or restoring the integrity of the endothelial glycocalyx, reversing the procoagulant and pro-inflammatory phenotype of injured endothelial cells and slowing renal fibrosis hold promise for the treatment of renal disease.

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Fig. 1: Role of the endothelium in health and disease.
Fig. 2: Endothelium dynamics in health and disease.
Fig. 3: Diverse populations of endothelial cells in the kidney.
Fig. 4: Renal diseases associated with endothelial injury in kidney diseases.
Fig. 5: Renal damage associated with defective endothelial protection.
Fig. 6: Endothelial dysfunction in common diseases.

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Acknowledgements

The authors are grateful to all members of the French Renal Endothelial Society (FRENDS) for fruitful discussions. FRENDS is a collaborative group of nephrologists and researchers working on the endothelium in different renal diseases. The research was supported by grants from the Agence Nationale de la Recherche (ANR) JCJC–INFLACOMP 2015–2018 (ANR-15-CE15-0001; to L.T.R.); INSERM (to L.T.R.); EU FP7 grant 2012–305608 (EURenOmics; to V.F.-B.); Assistance Publique-Hôpitaux de Paris (AP-HP)-Programme Hospitaliser de Recherche Clinique (PHRC) AOM08198 (to V.F.-B.); Association pour l'Information et la Recherche sur les maladies rénales Génétiques (AIRG) (to V.F.-B.); the French Society of Nephrology (to V.F.-B.); a grant from Appel d'Offre de Recherche Clinique (AORC) 2011-A01347 (to G.K.); and Assistance Publique-Hôpitaux de Marseille (AP-HM)-PHRC grant 2012-A00217-36 (to G.K.).

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All authors contributed to researching data for the article, discussing the article’s content and writing, reviewing and editing the manuscript before submission.

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Correspondence to Noemie Jourde-Chiche or Lubka T. Roumenina.

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F.F. has received consultancy fees and/or speaker honoraria from Alexion and Roche. M.L.Q. has received consultancy fees and/or speaker honoraria from Alexion. The other authors declare no competing interests.

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Supplementary Information

Glossary

Uraemic toxins

Blood compounds that are normally eliminated in the urine but accumulate in patients with chronic kidney disease or acute kidney injury and exert deleterious effects.

Flow-mediated dilation

Noninvasive, ultrasonography-based test of endothelial function that measures brachial arterial diameter in response to a substantial increase in arterial flow after the release of brachial constriction with a cuff. Flow-mediated dilation reflects the ability of endothelial cells to secrete nitric oxide (NO) and induce arterial vasodilation in response to shear stress. Alterations in flow-mediated dilation represent an early marker of endothelial dysfunction and can be reversed with endothelial recovery.

Tubulo-reticular inclusions

Cytoplasmic clusters of tubule-like structures arising from the membrane of the endoplasmic reticulum, thought to result from activation of type I interferons in endothelial cells and lymphocytes.

Intravital multiphoton microscopy

(IVM). A form of microscopy that enables the observation of biological processes in living animals (owing to its low energy and phototoxicity, which allow the prolonged exposure of tissues) with high resolution owing to the deep penetration of tissues by photons.

Oxidative burst

Also known as respiratory burst, oxidative burst is the rapid release of reactive oxygen species (ROS) from phagocytes (such as neutrophils or macrophages) to degrade internalized particles or pathogens within the phagosome. Primed neutrophils can also degranulate and undergo an oxidative burst in the absence of pathogens, as in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, leading to surrounding tissue damage.

Neutrophil extracellular traps

(NETs). NETs are composed of DNA in association with histones and granular proteins such as neutrophil elastase and myeloperoxidase (MPO). They are released by neutrophils in a process called NETosis, which allows pathogens to be captured in a bactericidal net and destroyed. NETs can also cause tissue damage, such as in ANCA-associated vasculitis, or increase the exposure of autoantigens to the immune system, such as in lupus.

Cell priming

Cell priming of neutrophils is the transition from a steady state with limited antimicrobial activity to an activated state, allowing the rapid enhancement of phagocytic activity and oxidative burst upon a second stimulation. Neutrophils can be primed by microbial products, chemo-attractants and inflammatory cytokines.

Azurophilic granules

Azurophilic granules of neutrophils are intracytoplasmic vesicles containing peptides with antimicrobial activity, such as MPO, proteinase 3 (PR3), α-defensins, elastase, cathepsin G and bactericidal/permeability increasing protein (BPI).

Histone-dependent cytotoxicity

Pro-inflammatory and cytotoxic signalling induced by extracellular histones. Histones and DNA normally reside in the nucleus and form nucleosomes. Extracellular histones are damage-associated molecular patterns (DAMPs), which elicit pro-inflammatory signalling through Toll-like receptors (TLRs) and promote cell death.

Opsonization

Tagging of a pathogen, a cell or an apoptotic body, with opsonins, which increases their interaction with phagocytes and natural killer (NK) cells. These opsonins can be antibodies (immunoglobulin G (IgG) or IgE) or complement fractions (C3b or C4b).

Heparanase

An enzyme that degrades polymeric heparan sulfate molecules into shorter-chain-length oligosaccharides. The action of heparanase disrupts the endothelial glycocalyx.

The polyol pathway

Pathway that converts hexose sugars such as glucose into sugar alcohols (polyols). In this metabolic pathway, glucose is reduced to sorbitol (by the aldose reductase), which is then converted to fructose (by sorbitol dehydrogenase). The polyol pathway is activated in hyperglycaemia, owing to the saturation of physiological glucose metabolism, and leads to a cellular oxidative stress.

Sorbitol

Sugar alcohol derived from glucose through the action of aldose reductase. Sorbitol is a component of the polyol pathway.

eNOS uncoupling

Occurs when endothelial NO synthase (eNOS) is not coupled with its substrate (mainly l-arginine) or cofactors. eNOS uncoupling results in the production of the pro-oxidative superoxide anion (O2) instead of NO, which characterizes endothelial dysfunction.

Prostanoids

Physiologically active lipid compounds that are metabolites of the fatty acid arachidonic acid. Prostanoids comprise prostaglandins (which have vasodilator and anti-aggregant properties) and thromboxanes (which are potent vasoconstrictors that also activate platelet aggregation).

Incretins

Glucose-lowering hormones secreted by the stomach during a meal. Incretins increase the release of insulin from pancreatic β-cells, slow gastric emptying and inhibit glucagon release from pancreatic α-cells. The two main incretins are glucagon-like peptide 1 (GLP1) and gastric inhibitory peptide (GIP), which are both rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP4).

Autoregulation

Autoregulation of renal blood is a homeostatic mechanism, relying both on myogenic response of afferent arterioles (vasoconstriction in case of transmural pressure elevation) and tubulo-glomerular feedback (depending on the sensing of sodium chloride delivery to the macula densa). Autoregulation protects the glomerular capillaries from elevations in arterial pressure and allows the kidney to maintain a fairly constant blood flow and glomerular filtration rate.

Indolic compounds

Chemical compounds comprising an aromatic bicyclic structure resembling that of indole (C8H7N). Indolic uraemic compounds result from tryptophan metabolism by the gut and include indoxyl sulfate, indole-3 acetic acid and indoxyl-β-d-glucuronide.

Dioxin

Also known as 2,3,7,8-tetrachlorodibenzodioxin (TCDD), dioxin and dioxin-like compounds are chemical pollutants of the environment, resulting from industrial practices (mostly incineration processes) and from forest fires and volcanic eruptions. Dioxin is the exogenous ligand of the transcription factor aryl hydrocarbon receptor (AhR). Exposure to dioxins, mostly through ingestion of contaminated food, is mutagenic and increases the risks of cardiovascular diseases.

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Jourde-Chiche, N., Fakhouri, F., Dou, L. et al. Endothelium structure and function in kidney health and disease. Nat Rev Nephrol 15, 87–108 (2019). https://doi.org/10.1038/s41581-018-0098-z

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