Hill, N. R. et al. Global prevalence of chronic kidney disease — a systematic review and meta-analysis. PLoS One 11, e0158765 (2016).
Himmelfarb, J., Vanholder, R., Mehrotra, R. & Tonelli, M. The current and future landscape of dialysis. Nat. Rev. Nephrol. 16, 573–585 (2020).
Matsushita, K. et al. Epidemiology and risk of cardiovascular disease in populations with chronic kidney disease. Nat. Rev. Nephrol. 18, 696–707 (2022).
Junho, C. V. C., Frisch, J., Soppert, J., Wollenhaupt, J. & Noels, H. Cardiomyopathy in chronic kidney disease: clinical features, biomarkers and the contribution of murine models in understanding pathophysiology. Clin. Kidney J. https://doi.org/10.1093/ckj/sfad085 (2023).
Jankowski, J., Floege, J., Fliser, D., Böhm, M. & Marx, N. Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation 143, 1157–1172 (2021).
Noels, H. & Jankowski, J. Increased risk of cardiovascular complications in chronic kidney disease: introduction to a compendium. Circ. Res. 132, 899–901 (2023).
Cases Amenós, A., González-Juanatey, J. R., Conthe Gutiérrez, P., Matalí Gilarranz, A. & Garrido Costa, C. Prevalence of chronic kidney disease in patients with or at a high risk of cardiovascular disease. Rev. Esp. Cardiol. 63, 225–228 (2010).
Wan, E. Y. F. et al. Burden of CKD and cardiovascular disease on life expectancy and health service utilization: a cohort study of Hong Kong Chinese hypertensive patients. J. Am. Soc. Nephrol. 30, 1991–1999 (2019).
Zoccali, C. & Mallamaci, F. Innate immunity system in patients with cardiovascular and kidney disease. Circ. Res. 132, 915–932 (2023).
Ebert, T. et al. Inflammation and oxidative stress in chronic kidney disease and dialysis patients. Antioxid. Redox Signal. 35, 1426–1448 (2021).
Schreibing, F., Anslinger, T. M. & Kramann, R. Fibrosis in pathology of heart and kidney: from deep RNA-sequencing to novel molecular TARGets. Circ. Res. 132, 1013–1033 (2023).
Baaten, C., Vondenhoff, S. & Noels, H. Endothelial cell dysfunction and increased cardiovascular risk in patients with chronic kidney disease. Circ. Res. 132, 970–992 (2023).
Hutcheson, J. D. & Goettsch, C. Cardiovascular calcification heterogeneity in chronic kidney disease. Circ. Res. 132, 993–1012 (2023).
Baaten, C. et al. Platelet abnormalities in CKD and their implications for antiplatelet therapy. Clin. J. Am. Soc. Nephrol. 17, 155–170 (2022).
Thakur, M. et al. NETs-induced thrombosis impacts on cardiovascular and chronic kidney disease. Circ. Res. 132, 933–949 (2023).
Ruiz-Ortega, M., Rayego-Mateos, S., Lamas, S., Ortiz, A. & Rodrigues-Diez, R. R. Targeting the progression of chronic kidney disease. Nat. Rev. Nephrol. 16, 269–288 (2020).
Yeung, C. K., Shen, D. D., Thummel, K. E. & Himmelfarb, J. Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport. Kidney Int. 85, 522–528 (2014).
Verbrugge, F. H., Tang, W. H. & Hazen, S. L. Protein carbamylation and cardiovascular disease. Kidney Int. 88, 474–478 (2015).
Schunk, S. J. et al. Guanidinylated apolipoprotein C3 (ApoC3) associates with kidney and vascular injury. J. Am. Soc. Nephrol. 32, 3146–3160 (2021). This study identified guanidinylated ApoC3 and its association with declining kidney function and cardiovascular events in patients with CKD, and revealed that guanidinylated ApoC3 promoted kidney fibrosis and reduced injury-induced endothelial regeneration in animal models.
Wang, Z. et al. Protein carbamylation links inflammation, smoking, uremia and atherogenesis. Nat. Med. 13, 1176–1184 (2007). This report identified the occurrence of protein carbamylation at sites of inflammation and atherosclerotic lesions through MPO-catalyzed oxidation of thiocyanate, and revealed that levels of carbamylated protein lysine residues predict cardiovascular event risk in individuals with largely preserved kidney function.
Delporte, C. et al. Myeloperoxidase-catalyzed oxidation of cyanide to cyanate: a potential carbamylation route involved in the formation of atherosclerotic plaques? J. Biol. Chem. 293, 6374–6386 (2018).
Berg, A. H. et al. Carbamylation of serum albumin as a risk factor for mortality in patients with kidney failure. Sci. Transl. Med. 5, 175ra129 (2013).
Kalim, S. et al. Protein carbamylation and the risk of ESKD in patients with CKD. J. Am. Soc. Nephrol. 34, 876–885 (2023).
Kalim, S. et al. Longitudinal changes in protein carbamylation and mortality risk after initiation of hemodialysis. Clin. J. Am. Soc. Nephrol. 11, 1809–1816 (2016).
Koeth, R. A. et al. Protein carbamylation predicts mortality in ESRD. J. Am. Soc. Nephrol. 24, 853–861 (2013).
Taes, Y. E. et al. Guanidino compounds after creatine supplementation in renal failure patients and their relation to inflammatory status. Nephrol. Dial. Transpl. 23, 1330–1335 (2008).
Schuett, K. et al. Clot structure: a potent mortality risk factor in patients on hemodialysis. J. Am. Soc. Nephrol. 28, 1622–1630 (2017).
Speer, T. et al. Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity 38, 754–768 (2013).
Zewinger, S. et al. Symmetric dimethylarginine, high-density lipoproteins and cardiovascular disease. Eur. Heart J. 38, 1597–1607 (2017). This work reported that the guanidine compound SDMA accumulated in HDL in patients with CKD, rendering HDL into a pro-inflammatory lipoprotein particle associated with increased mortality in CKD.
Sies, H. et al. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nat. Rev. Mol. Cell Biol. 23, 499–515 (2022).
Alhamdani, M. S., Al-Kassir, A. H., Jaleel, N. A., Hmood, A. M. & Ali, H. M. Elevated levels of alkanals, alkenals and 4-HO-alkenals in plasma of hemodialysis patients. Am. J. Nephrol. 26, 299–303 (2006).
Soulage, C. O. et al. Two toxic lipid aldehydes, 4-hydroxy-2-hexenal (4-HHE) and 4-hydroxy-2-nonenal (4-HNE), accumulate in patients with chronic kidney disease. Toxins 12, 567 (2020).
Miyata, T., Kurokawa, K. & van Ypersele de Strihou, C. Relevance of oxidative and carbonyl stress to long-term uremic complications. Kidney Int. Suppl. 76, S120–S125 (2000).
Mera, K. et al. Oxidation and carboxy methyl lysine-modification of albumin: possible involvement in the progression of oxidative stress in hemodialysis patients. Hypertens. Res. 28, 973–980 (2005).
Mitrogianni, Z., Barbouti, A., Galaris, D. & Siamopoulos, K. C. Oxidative modification of albumin in predialysis, hemodialysis, and peritoneal dialysis patients. Nephron Clin. Pract. 113, c234–c240 (2009).
Witko-Sarsat, V. et al. Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int. 49, 1304–1313 (1996).
Kaneda, H., Taguchi, J., Ogasawara, K., Aizawa, T. & Ohno, M. Increased level of advanced oxidation protein products in patients with coronary artery disease. Atherosclerosis 162, 221–225 (2002).
Cao, W., Hou, F. F. & Nie, J. AOPPs and the progression of kidney disease. Kidney Int. Suppl. 4, 102–106 (2014).
Valli, A. et al. Overestimation of advanced oxidation protein products in uremic plasma due to presence of triglycerides and other endogenous factors. Clin. Chim. Acta 379, 87–94 (2007).
Zhou, C. et al. Association between serum advanced oxidation protein products and mortality risk in maintenance hemodialysis patients. J. Transl. Med. 19, 284 (2021).
Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001).
Dozio, E. et al. Accelerated AGEing: the impact of advanced glycation end products on the prognosis of chronic kidney disease. Antioxidants 12, 584 (2023).
Stinghen, A. E., Massy, Z. A., Vlassara, H., Striker, G. E. & Boullier, A. Uremic toxicity of advanced glycation end products in CKD. J. Am. Soc. Nephrol. 27, 354–370 (2016).
Agalou, S., Ahmed, N., Babaei-Jadidi, R., Dawnay, A. & Thornalley, P. J. Profound mishandling of protein glycation degradation products in uremia and dialysis. J. Am. Soc. Nephrol. 16, 1471–1485 (2005).
Rabbani, N., Sebekova, K., Sebekova, K. Jr., Heidland, A. & Thornalley, P. J. Accumulation of free adduct glycation, oxidation, and nitration products follows acute loss of renal function. Kidney Int. 72, 1113–1121 (2007).
Uchiki, T. et al. Glycation-altered proteolysis as a pathobiologic mechanism that links dietary glycemic index, aging, and age-related disease (in nondiabetics). Aging Cell 11, 1–13 (2012).
Mallipattu, S. K., He, J. C. & Uribarri, J. Role of advanced glycation endproducts and potential therapeutic interventions in dialysis patients. Semin. Dial. 25, 529–538 (2012).
Ramazi, S. & Zahiri, J. Posttranslational modifications in proteins: resources, tools and prediction methods. Database 2021, baab012 (2021).
Cao, Y. et al. An overview of the posttranslational modifications and related molecular mechanisms in diabetic nephropathy. Front. Cell Dev. Biol. 9, 630401 (2021).
Wang, X., Liu, T., Huang, Y., Dai, Y. & Lin, H. Regulation of transforming growth factor-β signalling by SUMOylation and its role in fibrosis. Open. Biol. 11, 210043 (2021).
Aranda-Rivera, A. K., Cruz-Gregorio, A., Aparicio-Trejo, O. E. & Pedraza-Chaverri, J. Mitochondrial redox signaling and oxidative stress in kidney diseases. Biomolecules 11, 1144 (2021).
He, W. J. et al. Association of mitochondrial DNA copy number with risk of progression of kidney disease. Clin. J. Am. Soc. Nephrol. 17, 966–975 (2022).
Fazzini, F. et al. Mitochondrial DNA copy number is associated with mortality and infections in a large cohort of patients with chronic kidney disease. Kidney Int. 96, 480–488 (2019).
Afshinnia, F. et al. Myeloperoxidase levels and its product 3-chlorotyrosine predict chronic kidney disease severity and associated coronary artery disease. Am. J. Nephrol. 46, 73–81 (2017).
Vanholder, R., Pletinck, A., Schepers, E. & Glorieux, G. Biochemical and clinical impact of organic uremic retention solutes: a comprehensive update. Toxins 10, 33 (2018).
Harlacher, E., Wollenhaupt, J., Baaten, C. & Noels, H. Impact of uremic toxins on endothelial dysfunction in chronic kidney disease: a systematic review. Int. J. Mol. Sci. 23, 531 (2022).
Mera, K. et al. The structure and function of oxidized albumin in hemodialysis patients: its role in elevated oxidative stress via neutrophil burst. Biochem. Biophys. Res. Commun. 334, 1322–1328 (2005).
Rong, G. et al. Advanced oxidation protein products induce apoptosis in podocytes through induction of endoplasmic reticulum stress. J. Physiol. Biochem. 71, 455–470 (2015).
Iwao, Y. et al. CD36 is one of important receptors promoting renal tubular injury by advanced oxidation protein products. Am. J. Physiol. Renal Physiol. 295, F1871–F1880 (2008).
Li, H. Y. et al. Advanced oxidation protein products accelerate renal fibrosis in a remnant kidney model. J. Am. Soc. Nephrol. 18, 528–538 (2007).
Marsche, G. et al. Hypochlorite-modified albumin colocalizes with RAGE in the artery wall and promotes MCP-1 expression via the RAGE-Erk1/2 MAP-kinase pathway. FASEB J. 21, 1145–1152 (2007).
Chen, Y. et al. p53 SUMOylation mediates AOPP-induced endothelial senescence and apoptosis evasion. Front. Cardiovasc. Med. 8, 795747 (2021).
Liu, S. X. et al. Advanced oxidation protein products accelerate atherosclerosis through promoting oxidative stress and inflammation. Arterioscler. Thromb. Vasc. Biol. 26, 1156–1162 (2006).
Feng, W. et al. Advanced oxidation protein products aggravate cardiac remodeling via cardiomyocyte apoptosis in chronic kidney disease. Am. J. Physiol. Heart Circ. Physiol. 314, H475–H483 (2018).
Delporte, C. et al. Impact of myeloperoxidase-LDL interactions on enzyme activity and subsequent posttranslational oxidative modifications of apoB-100. J. Lipid Res. 55, 747–757 (2014).
Drożdż, D. et al. Oxidative stress biomarkers and left ventricular hypertrophy in children with chronic kidney disease. Oxid. Med. Cell Longev. 2016, 7520231 (2016).
Le Master, E. et al. Proatherogenic flow increases endothelial stiffness via enhanced CD36-mediated uptake of oxidized low-density lipoproteins. Arterioscler. Thromb. Vasc. Biol. 38, 64–75 (2018).
Soppert, J., Lehrke, M., Marx, N., Jankowski, J. & Noels, H. Lipoproteins and lipids in cardiovascular disease: from mechanistic insights to therapeutic targeting. Adv. Drug Deliv. Rev. 159, 4–33 (2020).
Hou, J. S. et al. Serum malondialdehyde-modified low-density lipoprotein is a risk factor for central arterial stiffness in maintenance hemodialysis patients. Nutrients 12, 2160 (2020).
Noels, H., Lehrke, M., Vanholder, R. & Jankowski, J. Lipoproteins and fatty acids in chronic kidney disease: molecular and metabolic alterations. Nat. Rev. Nephrol. 17, 528–542 (2021).
Moradi, H., Pahl, M. V., Elahimehr, R. & Vaziri, N. D. Impaired antioxidant activity of high-density lipoprotein in chronic kidney disease. Transl. Res. 153, 77–85 (2009).
Gao, X. et al. Oxidized high-density lipoprotein impairs the function of human renal proximal tubule epithelial cells through CD36. Int. J. Mol. Med. 34, 564–572 (2014).
Yao, S. et al. Oxidized high density lipoprotein induces macrophage apoptosis via Toll-like receptor 4-dependent CHOP pathway. J. Lipid Res. 58, 164–177 (2017).
Pérez, L. et al. OxHDL controls LOX-1 expression and plasma membrane localization through a mechanism dependent on NOX/ROS/NF-κB pathway on endothelial cells. Lab. Invest. 99, 421–437 (2019).
Honda, H. et al. Oxidized high-density lipoprotein as a risk factor for cardiovascular events in prevalent hemodialysis patients. Atherosclerosis 220, 493–501 (2012).
Marsche, G. et al. Plasma-advanced oxidation protein products are potent high-density lipoprotein receptor antagonists in vivo. Circ. Res. 104, 750–757 (2009).
Van Eck, M. et al. Increased oxidative stress in scavenger receptor BI knockout mice with dysfunctional HDL. Arterioscler. Thromb. Vasc. Biol. 27, 2413–2419 (2007).
Ok, E., Basnakian, A. G., Apostolov, E. O., Barri, Y. M. & Shah, S. V. Carbamylated low-density lipoprotein induces death of endothelial cells: a link to atherosclerosis in patients with kidney disease. Kidney Int. 68, 173–178 (2005).
Speer, T. et al. Carbamylated low-density lipoprotein induces endothelial dysfunction. Eur. Heart J. 35, 3021–3032 (2014).
Apostolov, E. O., Ray, D., Savenka, A. V., Shah, S. V. & Basnakian, A. G. Chronic uremia stimulates LDL carbamylation and atherosclerosis. J. Am. Soc. Nephrol. 21, 1852–1857 (2010).
Hörkkö, S., Huttunen, K., Kervinen, K. & Kesäniemi, Y. A. Decreased clearance of uraemic and mildly carbamylated low-density lipoprotein. Eur. J. Clin. Invest. 24, 105–113 (1994).
Sun, J. T. et al. Increased carbamylation level of HDL in end-stage renal disease: carbamylated-HDL attenuated endothelial cell function. Am. J. Physiol. Renal Physiol. 310, F511–F517 (2016).
Chang, C. T. et al. PON-1 carbamylation is enhanced in HDL of uremia patients. J. Food Drug Anal. 27, 542–550 (2019).
Tan, K. C. B. et al. Carbamylated lipoproteins and progression of diabetic kidney disease. Clin. J. Am. Soc. Nephrol. 15, 359–366 (2020).
Holzer, M. et al. Protein carbamylation renders high-density lipoprotein dysfunctional. Antioxid. Redox Signal. 14, 2337–2346 (2011).
Zewinger, S. et al. Serum amyloid A: high-density lipoproteins interaction and cardiovascular risk. Eur. Heart J. 36, 3007–3016 (2015).
Schuchardt, M. et al. Dysfunctional high-density lipoprotein activates Toll-like receptors via serum amyloid A in vascular smooth muscle cells. Sci. Rep. 9, 3421 (2019).
Holzer, M. et al. Uremia alters HDL composition and function. J. Am. Soc. Nephrol. 22, 1631–1641 (2011).
Shao, B. et al. A cluster of proteins implicated in kidney disease is increased in high-density lipoprotein isolated from hemodialysis subjects. J. Proteome Res. 14, 2792–2806 (2015).
Weichhart, T. et al. Serum amyloid A in uremic HDL promotes inflammation. J. Am. Soc. Nephrol. 23, 934–947 (2012).
Artl, A., Marsche, G., Lestavel, S., Sattler, W. & Malle, E. Role of serum amyloid A during metabolism of acute-phase HDL by macrophages. Arterioscler. Thromb. Vasc. Biol. 20, 763–772 (2000).
Jaisson, S. et al. Carbamylated albumin is a potent inhibitor of polymorphonuclear neutrophil respiratory burst. FEBS Lett. 581, 1509–1513 (2007).
Jaisson, S. et al. Impact of carbamylation on type I collagen conformational structure and its ability to activate human polymorphonuclear neutrophils. Chem. Biol. 13, 149–159 (2006).
Rueth, M. et al. Guanidinylations of albumin decreased binding capacity of hydrophobic metabolites. Acta Physiol. 215, 13–23 (2015).
Cohen, M. P., Shea, E., Chen, S. & Shearman, C. W. Glycated albumin increases oxidative stress, activates NF-κ B and extracellular signal-regulated kinase (ERK), and stimulates ERK-dependent transforming growth factor-β1 production in macrophage RAW cells. J. Lab. Clin. Med. 141, 242–249 (2003).
Higai, K., Satake, M., Nishioka, H., Azuma, Y. & Matsumoto, K. Glycated human serum albumin enhances macrophage inflammatory protein-1β mRNA expression through protein kinase C-δ and NADPH oxidase in macrophage-like differentiated U937 cells. Biochim. Biophys. Acta 1780, 307–314 (2008).
Rubenstein, D. A., Maria, Z. & Yin, W. Glycated albumin modulates endothelial cell thrombogenic and inflammatory responses. J. Diabetes Sci. Technol. 5, 703–713 (2011).
Bucala, R. et al. Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency. Proc. Natl Acad. Sci. USA 91, 9441–9445 (1994).
Hodgkinson, C. P., Laxton, R. C., Patel, K. & Ye, S. Advanced glycation end-product of low density lipoprotein activates the Toll-like 4 receptor pathway implications for diabetic atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 28, 2275–2281 (2008).
Chen, C. et al. Damage of uremic myocardium by p-cresyl sulfate and the ameliorative effect of klotho by regulating SIRT6 ubiquitination. Toxicol. Lett. 367, 19–31 (2022).
Winnik, S., Auwerx, J., Sinclair, D. A. & Matter, C. M. Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. Eur. Heart J. 36, 3404–3412 (2015).
Wang, Y. J., Paneni, F., Stein, S. & Matter, C. M. Modulating sirtuin biology and nicotinamide adenine diphosphate metabolism in cardiovascular disease — from bench to bedside. Front. Physiol. 12, 755060 (2021).
Grootaert, M. O. J. & Bennett, M. R. Sirtuins in atherosclerosis: guardians of healthspan and therapeutic targets. Nat. Rev. Cardiol. 19, 668–683 (2022).
London, G. M. et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol. Dial. Transpl. 18, 1731–1740 (2003).
Holmar, J. et al. Uremic toxins affecting cardiovascular calcification: a systematic review. Cells 9, 2428 (2020).
Sun, J. T. et al. Oxidized HDL, as a novel biomarker for calcific aortic valve disease, promotes the calcification of aortic valve interstitial cells. J. Cardiovasc. Transl. Res. 12, 560–568 (2019).
Tanikawa, T., Okada, Y., Tanikawa, R. & Tanaka, Y. Advanced glycation end products induce calcification of vascular smooth muscle cells through RAGE/p38 MAPK. J. Vasc. Res. 46, 572–580 (2009).
Koike, S. et al. Advanced glycation end-products induce apoptosis of vascular smooth muscle cells: a mechanism for vascular calcification. Int. J. Mol. Sci. 17, 1567 (2016).
Mori, D. et al. Protein carbamylation exacerbates vascular calcification. Kidney Int. 94, 72–90 (2018).
Jankowski, V. et al. Carbamylated sortilin associates with cardiovascular calcification in patients with chronic kidney disease. Kidney Int. 101, 574–584 (2022). This study reported that carbamylation of sortilin in patients with CKD was associated with cardiovascular calcification and revealed that, mechanistically, sortilin carbamylation enhanced osteogenic differentiation and calcification of vascular smooth muscle cells, which was further accelerated by sortilin binding to IL-6.
Alesutan, I. et al. Circulating uromodulin inhibits vascular calcification by interfering with pro-inflammatory cytokine signalling. Cardiovasc. Res. 117, 930–941 (2021).
Schurgers, L. J. et al. Post-translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification. J. Thromb. Haemost. 5, 2503–2511 (2007).
Schurgers, L. J. et al. The circulating inactive form of matrix Gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report. Clin. J. Am. Soc. Nephrol. 5, 568–575 (2010).
Schlieper, G. et al. Circulating nonphosphorylated carboxylated matrix Gla protein predicts survival in ESRD. J. Am. Soc. Nephrol. 22, 387–395 (2011).
Roumeliotis, S., Dounousi, E., Eleftheriadis, T. & Liakopoulos, V. Association of the inactive circulating matrix Gla protein with vitamin K intake, calcification, mortality, and cardiovascular disease: a review. Int. J. Mol. Sci. 20, 628 (2019).
Zhang, Y. et al. The ameliorative effect of terpinen-4-ol on ER stress-induced vascular calcification depends on SIRT1-mediated regulation of PERK acetylation. Pharmacol. Res. 170, 105629 (2021).
Yang, L. et al. Unspliced XBP1 counteracts β-catenin to inhibit vascular calcification. Circ. Res. 130, 213–229 (2022).
Carlisle, R. E. et al. TDAG51 induces renal interstitial fibrosis through modulation of TGF-β receptor 1 in chronic kidney disease. Cell Death Dis. 12, 921 (2021).
Ouyang, L. et al. Indoleamine 2,3-dioxygenase 1 deletion-mediated kynurenine insufficiency in vascular smooth muscle cells exacerbates arterial calcification. Circulation 145, 1784–1798 (2022).
Vanholder, R., Nigam, S. K., Burtey, S. & Glorieux, G. What if not all metabolites from the uremic toxin generating pathways are toxic? A hypothesis. Toxins 14, 221 (2022).
Wang, Y. et al. DUSP26 induces aortic valve calcification by antagonizing MDM2-mediated ubiquitination of DPP4 in human valvular interstitial cells. Eur. Heart J. 42, 2935–2951 (2021).
Choi, B. et al. Dipeptidyl peptidase-4 induces aortic valve calcification by inhibiting insulin-like growth factor-1 signaling in valvular interstitial cells. Circulation 135, 1935–1950 (2017).
Xu, T. H. et al. OGT-mediated KEAP1 glycosylation accelerates NRF2 degradation leading to high phosphate-induced vascular calcification in chronic kidney disease. Front. Physiol. 11, 1092 (2020).
Jin, D. et al. NRF2-suppressed vascular calcification by regulating the antioxidant pathway in chronic kidney disease. FASEB J. 36, e22098 (2022).
Yimamu, Y. et al. 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) induces ectopic calcification. J. Clin. Biochem. Nutr. 71, 103–111 (2022).
Torremadé, N. et al. Vascular calcification induced by chronic kidney disease is mediated by an increase of 1α-hydroxylase expression in vascular smooth muscle cells. J. Bone Min. Res. 31, 1865–1876 (2016).
Masbuchin, A. N., Rohman, M. S. & Liu, P. Y. Role of glycosylation in vascular calcification. Int. J. Mol. Sci. 22, 9829 (2021).
Grande, M. T. et al. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat. Med. 21, 989–997 (2015).
Gorisse, L. et al. Protein carbamylation is a hallmark of aging. Proc. Natl Acad. Sci. USA 113, 1191–1196 (2016).
Desmons, A. et al. Proteasome-dependent degradation of intracellular carbamylated proteins. Aging 11, 3624–3638 (2019).
Pietrement, C., Gorisse, L., Jaisson, S. & Gillery, P. Chronic increase of urea leads to carbamylated proteins accumulation in tissues in a mouse model of CKD. PLoS One 8, e82506 (2013).
Jaisson, S. et al. Carbamylation differentially alters type I collagen sensitivity to various collagenases. Matrix Biol. 26, 190–196 (2007).
Garnotel, R., Sabbah, N., Jaisson, S. & Gillery, P. Enhanced activation of and increased production of matrix metalloproteinase-9 by human blood monocytes upon adhering to carbamylated collagen. FEBS Lett. 563, 13–16 (2004).
Gilcrease, M. Z. & Hoover, R. L. Human monocyte interactions with non-enzymatically glycated collagen. Diabetologia 35, 160–164 (1992).
Wolffenbuttel, B. H. et al. Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc. Natl Acad. Sci. USA 95, 4630–4634 (1998).
Sell, D. R. & Monnier, V. M. Molecular basis of arterial stiffening: role of glycation — a mini-review. Gerontology 58, 227–237 (2012).
Ziyadeh, F. N., Han, D. C., Cohen, J. A., Guo, J. & Cohen, M. P. Glycated albumin stimulates fibronectin gene expression in glomerular mesangial cells: involvement of the transforming growth factor-β system. Kidney Int. 53, 631–638 (1998).
Chen, S., Cohen, M. P., Lautenslager, G. T., Shearman, C. W. & Ziyadeh, F. N. Glycated albumin stimulates TGF-β1 production and protein kinase C activity in glomerular endothelial cells. Kidney Int. 59, 673–681 (2001).
Cohen, M. P. et al. Inhibiting albumin glycation in vivo ameliorates glomerular overexpression of TGF-β1. Kidney Int. 61, 2025–2032 (2002).
Cohen, M. P. et al. Inhibiting albumin glycation ameliorates diabetic nephropathy in the db/db mouse. Exp. Nephrol. 8, 135–143 (2000).
Zhu, Q. et al. HUWE1 promotes EGFR ubiquitination and degradation to protect against renal tubulointerstitial fibrosis. FASEB J. 34, 4591–4601 (2020).
Saritas, T. et al. Disruption of CUL3-mediated ubiquitination causes proximal tubule injury and kidney fibrosis. Sci. Rep. 9, 4596 (2019).
Li, Y. et al. PTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney disease. J. Clin. Invest. 129, 1129–1151 (2019).
Hirschey, M. D. et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121–125 (2010).
Kang, H. M. et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat. Med. 21, 37–46 (2015).
Zhang, Y. et al. Sirtuin 3 regulates mitochondrial protein acetylation and metabolism in tubular epithelial cells during renal fibrosis. Cell Death Dis. 12, 847 (2021).
Lin, W. et al. Klotho restoration via acetylation of peroxisome proliferation-activated receptor γ reduces the progression of chronic kidney disease. Kidney Int. 92, 669–679 (2017).
Moreno, J. A. et al. The inflammatory cytokines TWEAK and TNFα reduce renal klotho expression through NFκB. J. Am. Soc. Nephrol. 22, 1315–1325 (2011).
Shen, F. & Zhuang, S. Histone acetylation and modifiers in renal fibrosis. Front. Pharmacol. 13, 760308 (2022).
Rauchman, M. & Griggs, D. Emerging strategies to disrupt the central TGF-β axis in kidney fibrosis. Transl. Res. 209, 90–104 (2019).
Xu, J., Zhou, L. & Liu, Y. Cellular senescence in kidney fibrosis: pathologic significance and therapeutic strategies. Front. Pharmacol. 11, 601325 (2020).
Ebert, T., Tran, N., Schurgers, L., Stenvinkel, P. & Shiels, P. G. Ageing — oxidative stress, PTMs and disease. Mol. Asp. Med. 86, 101099 (2022).
Shiels, P. G., McGuinness, D., Eriksson, M., Kooman, J. P. & Stenvinkel, P. The role of epigenetics in renal ageing. Nat. Rev. Nephrol. 13, 471–482 (2017).
Baaten, C. et al. Platelet function in CKD: a systematic review and meta-analysis. J. Am. Soc. Nephrol. 32, 1583–1598 (2021).
Pasterk, L. et al. Oxidized plasma albumin promotes platelet-endothelial crosstalk and endothelial tissue factor expression. Sci. Rep. 6, 22104 (2016).
Florens, N. et al. CKD increases carbonylation of HDL and is associated with impaired antiaggregant properties. J. Am. Soc. Nephrol. 31, 1462–1477 (2020).
Baralić, M. et al. Fibrinogen modification and fibrin formation in patients with an end-stage renal disease subjected to peritoneal dialysis. Biochemistry 85, 947–954 (2020).
Rubenstein, D. A. & Yin, W. Glycated albumin modulates platelet susceptibility to flow induced activation and aggregation. Platelets 20, 206–215 (2009).
Soaita, I., Yin, W. & Rubenstein, D. A. Glycated albumin modifies platelet adhesion and aggregation responses. Platelets 28, 682–690 (2017).
Binder, V. et al. Impact of fibrinogen carbamylation on fibrin clot formation and stability. Thromb. Haemost. 117, 899–910 (2017).
Binder, V. et al. Carbamylation of integrin αIIbβ3: the mechanistic link to platelet dysfunction in ESKD. J. Am. Soc. Nephrol. 33, 1841–1856 (2022). This study reported carbamylation of platelet integrin αIIbβ3 in patients with CKD, which interfered with integrin-mediated fibrinogen binding, platelet adhesion and aggregation, and might thus contribute to increased bleeding risk in CKD.
Lan, Q. et al. Renal klotho safeguards platelet lifespan in advanced chronic kidney disease through restraining Bcl-xL ubiquitination and degradation. J. Thromb. Haemost. 20, 2972–2987 (2022).
Chitalia, V. C. et al. Uremic serum and solutes increase post-vascular interventional thrombotic risk through altered stability of smooth muscle cell tissue factor. Circulation 127, 365–376 (2013).
Walker, J. A. et al. Indoleamine 2,3-dioxygenase-1, a novel therapeutic target for post-vascular injury thrombosis in CKD. J. Am. Soc. Nephrol. 32, 2834–2850 (2021).
Kannan, S., Krishnankutty, R. & Souchelnytskyi, S. Novel post-translational modifications in human serum albumin. Protein Pept. Lett. 29, 473–484 (2022).
Di Iorio, B. R. et al. Nutritional therapy reduces protein carbamylation through urea lowering in chronic kidney disease. Nephrol. Dial. Transplant. 33, 804–813 (2018).
Klahr, S. et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of diet in Renal Disease Study Group. N. Engl. J. Med. 330, 877–884 (1994).
Garneata, L., Stancu, A., Dragomir, D., Stefan, G. & Mircescu, G. Ketoanalogue-supplemented vegetarian very low-protein diet and CKD progression. J. Am. Soc. Nephrol. 27, 2164–2176 (2016).
Tang, M. et al. The impact of carbamylation and anemia on HbA1c’s association with renal outcomes in patients with diabetes and chronic kidney disease. Diabetes Care 46, 130–137 (2023).
Nicolas, C. et al. Carbamylation is a competitor of glycation for protein modification in vivo. Diabetes Metab. 44, 160–167 (2018).
Nicolas, C. et al. Carbamylation and glycation compete for collagen molecular aging in vivo. Sci. Rep. 9, 18291 (2019).
Weber, C. & Noels, H. Atherosclerosis: current pathogenesis and therapeutic options. Nat. Med. 17, 1410–1422 (2011).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05021835 (2024).
Jong, J. A. W. et al. A ninhydrin-type urea sorbent for the development of a wearable artificial kidney. Macromol. Biosci. 20, e1900396 (2020).
Sternkopf, M. et al. A bifunctional adsorber particle for the removal of hydrophobic uremic toxins from whole blood of renal failure patients. Toxins 11, 389 (2019).
Kalim, S. et al. The effects of parenteral amino acid therapy on protein carbamylation in maintenance hemodialysis patients. J. Ren. Nutr. 25, 388–392 (2015). First proof-of concept investigation of amino acid therapy aimed at reducing protein carbamylation in patients receiving haemodialysis; demonstrated that scavenging reactive metabolites in the plasma of patients receiving haemodialysis can decrease albumin carbamylation.
Delanghe, S., Delanghe, J. R., Speeckaert, R., Van Biesen, W. & Speeckaert, M. M. Mechanisms and consequences of carbamoylation. Nat. Rev. Nephrol. 13, 580–593 (2017).
Descamps-Latscha, B. et al. Early prediction of IgA nephropathy progression: proteinuria and AOPP are strong prognostic markers. Kidney Int. 66, 1606–1612 (2004).
Descamps-Latscha, B. et al. Advanced oxidation protein products as risk factors for atherosclerotic cardiovascular events in nondiabetic predialysis patients. Am. J. Kidney Dis. 45, 39–47 (2005).
Zhou, Q. et al. Accumulation of circulating advanced oxidation protein products is an independent risk factor for ischaemic heart disease in maintenance haemodialysis patients. Nephrology 17, 642–649 (2012).
Zeng, L. et al. Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease-accelerated atherosclerosis. J. Biol. Chem. 293, 7238–7249 (2018).
- The Renal Warrior Project. Join Now
- Source: https://www.nature.com/articles/s41581-024-00837-x