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Uremia and endothelial cells
- 1. Uremia and Endothelial Cells Pr S. Burtey Centre de néphrologie et transplantation rénale Vascular Resarch Center Marseille Marseille
- 2. Confluence of interest • Otsuka • Amgen • Fresenius • Gambro • Alexion • I’m nephrologist • I lead a team working on uremic toxins and endothelial cells JAMA. 2015;314(17):1791-1792 “Fear is the enemy of logic.”
- 3. Endothelium • A tissu, in fact numerous tissues • Surface: 3000 to 6000 m2 • Thickness: 2 µm • Weight: 720 g (600 g of capillaries) • Each organ has its endothelium • Transcriptome • Patterns of Receptors • Ability to react to an agression • Artery Vs Vein Vs capillary Physiological Reviews Vol. 89 no. 4, 1269-1339
- 4. Endothelial Functions Endothelial Cell Metabolism Angiogenesis Vascular permeability Vascular tone Control of vSMC proliferation NO H2S PGI2 Endothelin TXA2 PGH2 Hemostasis TM Glycocalyx T-PA TFPI PGI2 vWF TF TXA2 PAI-1 Inflammation Leucocytes traffic ICAM1, VCAM, E-Selectin, MCP1
- 5. Endothelial dysfunction • A defect of endothelium to produce NO. • Evaluation: • Flow-mediated vasodilatation et Tonometry (Tousoulis et al. Pharmacology & Therapeutics 144 (2014) 253–267) • Biomarkers (Walczak et al. Pharmacological Reports 67 (2015) 771–777) Furchgott, Nobel 1998 Healthy Endothelium Vasodilatator (NO,H2S, PGI2) Minimal oxydative stress Anticoagulant (t-Pa, TFPI, Glycocalyx) Anti-inflammatory Balance lesion-regeneration in favor of regeneration Unhealthy Endothelium Defect in Vasodilatation Increased oxydative stress Procoagulant (vWF, Tissue Factor, PAI-1) Pro-inflammatory (ICAM,VCAM, E- Selectin, MCP-1, IL6, TNF) Reduced regeneration potentienal (reduced number of progenitors, Increase in eMP ) Lost of glycocalyx (endocan) Hyperglycemia Blood Pressure Turbulent flow Ox-LDL Inflammation Tobacco ROS AGEs Obesity Aging
- 6. Clinical impact of endothelial dysfunction World J Cardiol 2014; 6(8): 824-835
- 7. Why nephrologist must be aware of endothelium ?
- 8. Is the endothelium dysfunctionnal during CKD? • Yes and at each stage. Hirata et al. International Journal of Cardiology 173 (2014) 481–486 eGFR: 50 ml/mn Chen et al. PLoS ONE 2015 10(7): e0132047 eGFR: 43 ml/mn Jourde-Chiche et al. Seminars in dialysis 2011 p327–337 Recio-Mayoral et al. / Atherosclerosis 216 (2011) 446–451 Verbeke et al. Clin J Am Soc Nephrol 6: 2009–2015, 2011
- 9. Unhealthy endothelium and AVF Hemodialysis Fistula Maturation Study Group Resistance to NO
- 10. Endothelial dysfunction during CKD Uremic Toxins Healthy Endothelium Vasodilatator (NO,H2S, PGI2) Minimal oxydative stress Anticoagulant (t-Pa, TFPI, Glycocalyx) Anti-inflammatory Balance lesion-regeneration in favor of regeneration Malfunctionning Endothelium Defect in Vasodilatation Increased oxydative stress Procoagulant (vWF, Tissue Factor, PAI-1) Pro-inflammatory (ICAM,VCAM, E- Selectin, MCP-1, IL6, TNF) Reduced regeneration potentienal (reduced number of progenitors, Increase in eMP ) Lost of glycocalyx (endocan) Hyperglycemia Blood Pressure Turbulent flow Ox-LDL Inflammation Tobacco ROS AGEs Obesity Aging
- 11. One of the strongest proof is given by the kidney donor. Rossi et al. Transplantation 2014;97: 548Y554)
- 12. Uremic Toxins • Glomerular flow rate decline is associated with retention of solutes: • Negative interactions with biological functions • Association with clinical events • Three families • Free water-soluble low molecular mass compounds (<0.5 kD) • Middle molecules • Protein-bound solutes http://uremic-toxins.org/
- 13. 131313 Phosphore AGEs HDL Free water-soluble LMW molecules Protein-bound solutesMiddle molecules
- 14. ADMA and SDMA
- 15. HDL cholesterol Endothelial cell elixir of youth In CKD, pure evil Speer et al. Nephrol Dial Transplant (2013) 28: 2456–2463
- 16. AGEs Increase oxydative stress Reduced expression of eNOS Lower production of NO Reduced endothelial progenitors Reduced PGI2 Increase ET-1 Stinghen et al. JASN 2015
- 17. Phosphate Gross et al. Circulation Journal Vol. 78 (2014) p. 2339-2346 FMD Stevens et al. Lancet. 2015 Feb 26;385 Suppl 1:S10 Silswal et al. Am J Physiol Endocrinol Metab 307: E426–E436, 2014 And FGF-23?
- 18. Para-cresyl sulfate • Endothelial toxicity is mainly mediated by leucocytes. • On HUVECs, PCS increase the production of ROS (Gross et al. J. Cell. Physiol. 230: 2927– 2935, 2015). • Increase of ROS is secondary to NOX activation.
- 19. Indoles Clinical effects Biological Effects Reduced proliferation of endothelial cells Increased production of ROS Increased production of endothelial microparticules Reduced production of NO Increased interactions betwen leucocytes and EC. Loss of glycocalyx Reduced number of EPC and impaired neovascularisation Senescence Dou, Sallée et al , Jasn 2015 IAAIS Barreto et al, cJasn 2009 MortalityCVEvents Vanholder et al, JASN 2014
- 20. Indoles Vanholder et al, JASN 2014
- 21. Indoles • What happened if we reduce the concentration of IS? Six et al. Atherosclerosis 243 (2015) 248e256Yu et al. Clin J Am Soc Nephrol 6: 30–39, 2011
- 22. Indoles and Aryl Hydrocarbon Receptor IS IAA Atherothrombosis JASN April 2015 vol. 26 no. 4 876-887 AhR F3,PTGS2 CYP1A1,CYP1A2 TF COX2 P38 MAPK NF-KB NF-KB Inflammation Coagulation Endothelial Cell
- 23. Indoles and endothelial progenitors
- 24. The Moirai and endothelium Klotho protects endothelium As Atropos, indoxyl sulfate
- 25. How to restore healthy endothelium? • Reducing the amount of uremic toxins • Production • Purification • Statins • Inh of ROS ? • Soluble Klotho? • Inh of AhR ? Zafeiropoulou K. PLoS ONE 7(2): e30975
- 26. How to restore healthy endothelium? Cocoa Flavanols
- 27. Conclusion • Endothelium is activated during CKD. • It plays a role in the increased CV of patients with CKD. • Uremic toxins induce directly or indirectly activation of endothelium. • Activation of AhR during CKD activates endothelium • Procoagulant • Inflammatory. • Chocolate is perhaps the future cure of unhealthy endothelium during CKD.
- 28. An introduction to the talk of Griet Glorieux
Editor's Notes
- Ladies and gentlemen good morning, I thank the organizators to give the opportunity to talk about the impact of uremic toxins on endothelial cells
- First my confluenc of interest, i think the main one is that I have a group working on uremic toxins and EC.
- Endothelium is a real tissue, in fact numerous tissues as the number of organs or subregion in organ. As you know for exemple the glomerular endothelium is different from the peritubular. Endothelium is a large organe but thin organe, its thickness is the thikness of the monolayer of endothelial cell. Each organ have its endothelium with its transcriptomic landscape, its pattern of receptor and various properities. IN addition you could differentiate in each organ arteries, veins endothelium and capollary beds with various functions
- Endothelium controls the vascular tone mainly by the balance betwen nitrous oxyde ad endothelin. It control the vacular permeability and the proliferation of vascular smooth muscle cell. Endothelium plays important role in inflammation mainly by controlin the leucocytes traffic from blood to the tissues. One of its most important fonction is hemostatis. It could produce numerous protein involved in primary hemostasis, coagulation and fibrinolysis. Finally it plays a role in angiogenesis normal and pathologic and the metabolism of tissues via its permability.
- Endothelium could dysfunction, the main marker of it its inability to produce NO. In fact it could be better to talk of a transition from an healthy to an unhealthy endothelume. Healthy iis vasodilatation the unhealthy is defective, the healthy have a low level of oxydative stress, and it avoid formation of clots the unhealthy is clearly procoagulant and proinflamatory. And fiany the balance between lesion and regenration and lost of glycocalyx. Numerous causes could induce activation of endothelium frome physiological like aging to exposur to tobacco. You could evaluate the health of the endotheiluum by its ability to release NO and you study the flow mediated vasodilatation or you measure various biomarkers produce by unhealthy endothelium.
- In general population there is a large amount of studies showing a relation betwen endothelial dysfunction and cardiovascular risk.
- As you know CKD is associated with an increased cardiovascular risk. The traditionnal risk factor di not explain the overrisk. So major endothelial dysfunction could be a mediator of CV risk during CKD.
- The endothelium during CKD is unhealthy and associated with and increase risk of CV events. The level of dysfunction prodress with CKD and regress with successful kidney transplantation.
- IN addition it is also associated with the risk of dysfunctionnal arteriovenous fistula in human and rodents. As you can see. The severity of ED is associated with a reduced diameter and flow in the AVF interestingly the same results was observed in rat with CKD compared to control. SO endothelium could control the patency of vascular access.
- During CKD beside traditionnals aggresors of the endotelium one unique is present: the uremic toxins
- The best proof of the role of the uremic toxins could induced endothelial dysfunction is provide by this australian study. They measure two uremic toxin and endothelial function in kidney donor and they observed n increase of uremic toxins and an impaired endothelium function.
- Uremic toxins are solute accumulationg with the GFR loss. A uremic toxins induce impairment of biological process and/or is associated with clinical events. 3 families of uremce toxins
- I choosed to talk of toxins with a well documented effects on EC. I will not talf of Il6, TNF a,d homocysteine they could be endtheliotoxine
- ADMA and SDMA accumulate during CKD and induced endothelial dysfunction mainly by inhibition of NOS. They are clearly associated with an increase of CV risk.
- HDL cholesterol is the endothelium elixir of youth, it improves all the parameter antiinflamatory, limitation of ROS, but in CKD it is pure evil inducing endothelial dysfunction by various phenomenom. Interestingly recently gene variant inducing raise in HDL is also associated with heart diseases.
- Ages accumulation during CKD is also associated with endothelial dysfunction by increasing oxydative stress ther reduced enos activity, dmminished the number of endothelial progenitor ena indced expression of endothelin 1
- Phosphate induced endothelial dusfunction with diminshed production of nos in ducing a limited FMS in patient, apoptosis of EC. FGF 23could also directly limited the production of NO.
- For a long time, we think that endothelial toxicity of PCS was secondary to leucocytes. Two recent papers show us that PCS could induced and increase ROS production directly by the EC. In the latter paper published recently in kidney international this increase is secondary to NOX activation. This lead to inflammationof the vessel with infliltration of the vessel bymonocyte.
- The indoles are important endotheliotoxins. They impaired all the normal function of endothelium.
- The mecanismm was mainly the increased expression of ROS. As you can see ion this slide, the only other protein directily increased was the e selectin.
- Th indoles clearly play a rol in vivo in the endothelial function as you can see here, if we reduced the amount of circulating is with AST-120 we imporve the endothelial function in human and in mice.
- In addition recently indole were show to reduced the regeneration of endothelial cells in a model of the lim ischemia in mouse. As you can see the bllod flow in the limb is impaired in the CKD ou IS injected mice and it is restaured with AST-120. the pathway interestingly is very closed with AhR pathways with a reduction in the expression of HIF1 that reduced the angiogenic functions of progenitor.
- Il a été montré que lklotho porotége l’endothélium de la senescence dans plusieurs articles dont vous avez ici avec en particulier une diminution de la senescence quand les cellules endothéliale sont exposé à du klotho soluble. SI la perte du parenchyme rénale diminue la production de klotho, il est cetainement que l’IS coupe la productiond e klotho au niveau rénale par au moins deux phénomènes induction de ROS et modulation de la méthylation du promoteur de klotho. De plus si l’IS entraine une dysfonction endothéliale, klotho est capable de la corriger du moins in vitro.
- Que faire pour améliorer cette dysfonction endothéliale? Diminuer les taux de toxines soit sur la production soit en les éliminants et cette article montre que la dialyse élimine des solutés qui inhibe le wound healing par exemple. Les statines avec la limite de l’augmentation des HDL, les inh de ROS comme la NAC, Klotho soluble en perfusion et peut être qu’en plus de l’Epo nous ferons du sklotho à nos patients, enfin mais j’ai un très conflits d’intérêts intellectuel c’est l’inhibition de l’activation d’Ahr.
- We are in Vienna and everybody knows the quality of the chocolate in this town. Perhaps, the solution to endothelium dysfnction will be to give chocolate to our patients. A recent paper in cJASN suggest it. Ingestion of cocoa flavanols improve the endothelial function as you can see here, reduced sdiastolic blood pressure and very intersteingly given at the befginning of the HD reduced the endothelial dysfunction induced by the technique. So perhaps we have to do a prescription of chocolate to our patients.
- As an introduction to the talk of griet, I like to show you an impressive video from this article published this month. In the brain the repair of small vessels need the help of macrophage. You see here the defect induced by laser shot, the macrophage arrive in green to pull on the endothelial cells to reconnect it. I thing it is a good illustration of the importance of leucocyte to maintain healthy blood vessels. Thank you for your attention.