Carnosine and Kidney Diseases: What We Currently Know?

Katarzyna        Kilis-Pstrusinska
doi:10.2174/0929867326666190730130024
Abstract

Carnosine (beta-alanyl-L-histidine) is an endogenously synthesised dipeptide which is present in different human tissues e.g. in the kidney. Carnosine is degraded by enzyme serum carnosinase, encoding by CNDP1 gene. Carnosine is engaged in different metabolic pathways in the kidney. It reduces the level of proinflammatory and profibrotic cytokines, inhibits advanced glycation end products’ formation, moreover, it also decreases the mesangial cell proliferation. Carnosine may also serve as a scavenger of peroxyl and hydroxyl radicals and a natural angiotensin-converting enzyme inhibitor.
This review summarizes the results of experimental and human studies concerning the role of carnosine in kidney diseases, particularly in chronic kidney disease, ischemia/reperfusion-induced acute renal failure, diabetic nephropathy and also drug-induced nephrotoxicity. The interplay between serum carnosine concentration and serum carnosinase activity and polymorphism in the CNDP1 gene is discussed.
Carnosine has renoprotective properties. It has a promising potential for the treatment and prevention of different kidney diseases, particularly chronic kidney disease which is a global public health issue. Further studies of the role of carnosine in the kidney may offer innovative and effective strategies for the management of kidney diseases.
Keywords: Carnosine, serum carnosinase, CNDP1 gene, chronic kidney disease, diabetic nephropathy, renoprotection.
« Previous Next »
[1] 
Drozak, J.; Veiga-da-Cunha, M.; Vertommen, D.; Stroobant, V.; Van Schaftingen, E. Molecular identification of carnosine synthase as ATP-grasp domain-containing protein 1 (ATPGD1). J. Biol. Chem.,  2010, 285(13), 9346-9356.
[http://dx.doi.org/10.1074/jbc.M109.095505] [PMID: 20097752] 
[2] 
Boldyrev, A.A.; Aldini, G.; Derave, W. Physiology and pathophysiology of carnosine. Physiol. Rev.,  2013, 93(4), 1803-1845.
[http://dx.doi.org/10.1152/physrev.00039.2012] [PMID: 24137022] 
[3] 
Peters, V.; Klessens, C.Q.; Baelde, H.J.; Singler, B.; Veraar, K.A.; Zutinic, A.; Drozak, J.; Zschocke, J.; Schmitt, C.P.; de Heer, E. Intrinsic carnosine metabolism in the human kidney. Amino Acids,  2015, 47(12), 2541-2550.
[http://dx.doi.org/10.1007/s00726-015-2045-7] [PMID: 26206726] 
[4] 
Quinn, P.J.; Boldyrev, A.A.; Formazuyk, V.E. Carnosine: its properties, functions and potential therapeutic applications. Mol. Aspects Med.,  1992, 13(5), 379-444.
[http://dx.doi.org/10.1016/0098-2997(92)90006-L] [PMID: 9765790] 
[5] 
Ng, R.H.; Marshall, F.D. Regional and subcellular distribution of homocarnosine-carnosine synthetase in the central nervous system of rats. J. Neurochem.,  1978, 30(1), I87-I90.
[http://dx.doi.org/10.1111/j.1471-4159.1978.tb07051.x] [PMID: 621500] 
[6] 
Harding, J.W.; O’Fallon, J.V. The subcellular distribution of carnosine, carnosine synthetase, and carnosinase in mouse olfactory tissues. Brain Res.,  1979, 173(1), 99-109.
[http://dx.doi.org/10.1016/0006-8993(79)91099-0] [PMID: 487087] 
[7] 
Lenney, J.F.; George, R.P.; Weiss, A.M.; Kucera, C.M.; Chan, P.W.; Rinzler, G.S. Human serum carnosinase: characterization, distinction from cellular carnosinase, and activation by cadmium. Clin. Chim. Acta,  1982, 123(3), 221-231.
[http://dx.doi.org/10.1016/0009-8981(82)90166-8] [PMID: 7116644] 
[8] 
Teufel, M.; Saudek, V.; Ledig, J.P.; Bernhardt, A.; Boularand, S.; Carreau, A.; Cairns, N.J.; Carter, C.; Cowley, D.J.; Duverger, D.; Ganzhorn, A.J.; Guenet, C.; Heintzelmann, B.; Laucher, V.; Sauvage, C.; Smirnova, T. Sequence identification and characterization of human carnosinase and a closely related non-specific dipeptidase. J. Biol. Chem.,  2003, 278(8), 6521-6531.
[http://dx.doi.org/10.1074/jbc.M209764200] [PMID: 12473676] 
[9] 
Sale, C.; Artioli, G.G.; Gualano, B.; Saunders, B.; Hobson, R.M.; Harris, R.C. Carnosine: from exercise performance to health. Amino Acids,  2013, 44(6), 1477-1491.
[http://dx.doi.org/10.1007/s00726-013-1476-2] [PMID: 23479117] 
[10] 
Artioli, G.G.; Sale, C.; Jones, R.L. Carnosine in health and disease. Eur. J. Sport Sci.,  2018, 1-10.
[http://dx.doi.org/10.1080/17461391.2018.1444096] [PMID: 29502490] 
[11] 
Hipkiss, A.R.; Baye, E.; de Courten, B. Carnosine and the processes of ageing. Maturitas,  2016, 93, 28-33.
[http://dx.doi.org/10.1016/j.maturitas.2016.06.002] [PMID: 27344459] 
[12] 
Baye, E.; Ukropcova, B.; Ukropec, J.; Hipkiss, A.; Aldini, G.; de Courten, B. Physiological and therapeutic effects of carnosine on cardiometabolic risk and disease. Amino Acids,  2016, 48(5), 1131-1149.
[http://dx.doi.org/10.1007/s00726-016-2208-1] [PMID: 26984320] 
[13] 
Hoffman, J.R.; Varanoske, A.; Stout, J.R. Effects of β-alanine supplementation on carnosine elevation and physiological performance. Adv. Food Nutr. Res.,  2018, 84, 183-206.
[http://dx.doi.org/10.1016/bs.afnr.2017.12.003] [PMID: 29555069] 
[14] 
Daniel, H.; Kottra, G. The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology. Pflugers Arch.,  2004, 447(5), 610-618.
[http://dx.doi.org/10.1007/s00424-003-1101-4] [PMID: 12905028] 
[15] 
Verri, T.; Barca, A.; Pisani, P.; Piccinni, B.; Storelli, C.; Romano, A. Di- and tripeptide transport in vertebrates: the contribution of teleost fish models. J. Comp. Physiol. B,  2017, 187(3), 395-462.
[http://dx.doi.org/10.1007/s00360-016-1044-7] [PMID: 27803975] 
[16] 
Lee, Y.T.; Hsu, C.C.; Lin, M.H.; Liu, K.S.; Yin, M.C. Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur. J. Pharmacol.,  2005, 513(1-2), 145-150.
[http://dx.doi.org/10.1016/j.ejphar.2005.02.010] [PMID: 15878720] 
[17] 
Son, D.O.; Satsu, H.; Kiso, Y.; Totsuka, M.; Shimizu, M. Inhibitory effect of carnosine on interleukin-8 production in intestinal epithelial cells through translational regulation. Cytokine,  2008, 42(2), 265-276.
[http://dx.doi.org/10.1016/j.cyto.2008.02.011] [PMID: 18397832] 
[18] 
Köppel, H.; Riedl, E.; Braunagel, M.; Sauerhoefer, S.; Ehnert, S.; Godoy, P.; Sternik, P.; Dooley, S.; Yard, B.A. L-carnosine inhibits high-glucose-mediated matrix accumulation in human mesangial cells by interfering with TGF-β production and signalling. Nephrol. Dial. Transplant.,  2011, 26(12), 3852-3858.
[http://dx.doi.org/10.1093/ndt/gfr324] [PMID: 21750159] 
[19] 
Liu, B.F.; Miyata, S.; Hirota, Y.; Higo, S.; Miyazaki, H.; Fukunaga, M.; Hamada, Y.; Ueyama, S.; Muramoto, O.; Uriuhara, A.; Kasuga, M. Methylglyoxal induces apoptosis through activation of p38 mitogen-activated protein kinase in rat mesangial cells. Kidney Int.,  2003, 63(3), 947-957.
[http://dx.doi.org/10.1046/j.1523-1755.2003.00829.x] [PMID: 12631075] 
[20] 
Alhamdani, M.S.; Al-Azzawie, H.F.; Abbas, F.K. Decreased formation of advanced glycation end-products in peritoneal fluid by carnosine and related peptides. Perit. Dial. Int.,  2007, 27(1), 86-89.
[PMID: 17179517] 
[21] 
Fatih Aydın, A.; Küçükgergin, C.; Bingül, İ.; Doğan-Ekici, I.; Doğru-Abbasoğlu, S.; Uysal, M. Effect of carnosine on renal function, oxidation and glycation products in the kidneys of high-fat diet/streptozotocin-induced diabetic rats. Exp. Clin. Endocrinol. Diabetes,  2017, 125(5), 282-289.
[http://dx.doi.org/10.1055/s-0043-100117] [PMID: 28407658] 
[22] 
Hipkiss, A.R.; Worthington, V.C.; Himsworth, D.T.; Herwig, W. Protective effects of carnosine against protein modification mediated by malondialdehyde and hypochlorite. Biochim. Biophys. Acta,  1998, 1380(1), 46-54.
[http://dx.doi.org/10.1016/S0304-4165(97)00123-2] [PMID: 9545530] 
[23] 
Jia, H.; Qi, X.; Fang, S.; Jin, Y.; Han, X.; Wang, Y.; Wang, A.; Zhou, H. Carnosine inhibits high glucose-induced mesangial cell proliferation through mediating cell cycle progression. Regul. Pept.,  2009, 154(1-3), 69-76.
[http://dx.doi.org/10.1016/j.regpep.2008.12.004] [PMID: 19154760] 
[24] 
Keshk, W.A.; Katary, M.A. Transforming growth factor-β1/Smad3 signaling and redox status in experimentally induced nephrotoxicity: impact of carnosine. Indian J. Clin. Biochem.,  2017, 32(1), 19-25.
[http://dx.doi.org/10.1007/s12291-016-0564-y] [PMID: 28149008] 
[25] 
Alpsoy, L.; Akcayoglu, G.; Sahin, H. Anti-oxidative and anti-genotoxic effects of carnosine on human lymphocyte culture. Hum. Exp. Toxicol.,  2011, 30(12), 1979-1985.
[http://dx.doi.org/10.1177/0960327111404908] [PMID: 21464095] 
[26] 
Aydín, A.F.; Küskü-Kiraz, Z.; Doğru-Abbasoğlu, S.; Uysal, M. Effect of carnosine treatment on oxidative stress in serum, apoB-containing lipoproteins fraction and erythrocytes of aged rats. Pharmacol. Rep.,  2010, 62(4), 733-739.
[http://dx.doi.org/10.1016/S1734-1140(10)70331-5] [PMID: 20885014] 
[27] 
Chan, W.K.; Decker, E.A.; Chow, C.K.; Boissonneault, G.A. Effect of dietary carnosine on plasma and tissue antioxidant concentrations and on lipid oxidation in rat skeletal muscle. Lipids,  1994, 29(7), 461-466.
[http://dx.doi.org/10.1007/BF02578242] [PMID: 7968266] 
[28] 
Gariballa, S.E.; Sinclair, A.J. Carnosine: physiological properties and therapeutic potential. Age Ageing,  2000, 29(3), 207-210.
[http://dx.doi.org/10.1093/ageing/29.3.207] [PMID: 10855900] 
[29] 
Guiotto, A.; Calderan, A.; Ruzza, P.; Borin, G. Carnosine and carnosine-related antioxidants: a review. Curr. Med. Chem.,  2005, 12(20), 2293-2315.
[http://dx.doi.org/10.2174/0929867054864796] [PMID: 16181134] 
[30] 
Yapislar, H.; Taskin, E. L-carnosine alters some hemorheologic and lipid peroxidation parameters in nephrectomized rats. Med. Sci. Monit.,  2014, 20, 399-405.
[http://dx.doi.org/10.12659/MSM.890528] [PMID: 24614724] 
[31] 
Hou, W.C.; Chen, H.J.; Lin, Y.H. Antioxidant peptides with Angiotensin converting enzyme inhibitory activities and applications for Angiotensin converting enzyme purification. J. Agric. Food Chem.,  2003, 51(6), 1706-1709.
[http://dx.doi.org/10.1021/jf0260242] [PMID: 12617609] 
[32] 
Peters, V.; Riedl, E.; Braunagel, M.; Höger, S.; Hauske, S.; Pfister, F.; Zschocke, J.; Lanthaler, B.; Benck, U.; Hammes, H.P.; Krämer, B.K.; Schmitt, C.P.; Yard, B.A.; Köppel, H. Carnosine treatment in combination with ACE inhibition in diabetic rats. Regul. Pept.,  2014, 194-195, 36-40.
[http://dx.doi.org/10.1016/j.regpep.2014.09.005] [PMID: 25234296] 
[33] 
Peters, V.; Schmitt, C.P.; Zschocke, J.; Gross, M.L.; Brismar, K.; Forsberg, E. Carnosine treatment largely prevents alterations of renal carnosine metabolism in diabetic mice. Amino Acids,  2012, 42(6), 2411-2416.
[http://dx.doi.org/10.1007/s00726-011-1046-4] [PMID: 21833769] 
[34] 
Elbarbary, N.S.; Ismail, E.A.R.; El-Naggar, A.R.; Hamouda, M.H.; El-Hamamsy, M. The effect of 12 weeks carnosine supplementation on renal functional integrity and oxidative stress in pediatric patients with diabetic nephropathy: a randomized placebo-controlled trial. Pediatr. Diabetes,  2018, 19(3), 470-477.
[http://dx.doi.org/10.1111/pedi.12564] [PMID: 28744992] 
[35] 
Arinsoy, T.; Deger, S.M.; Ates, K.; Altun, B.; Ecder, T.; Camsari, T.; Serdengecti, K.; Suleymanlar, G. Prevalence of chronic kidney disease in turkish adults with obesity and metabolic syndrome: a post hoc analysis from chronic renal disease in turkey study. J. Ren. Nutr.,  2016, 26(6), 373-379.
[http://dx.doi.org/10.1053/j.jrn.2016.08.004] [PMID: 27641823] 
[36] 
Coombes, J.S.; Fassett, R.G. Antioxidant therapy in hemodialysis patients: a systematic review. Kidney Int.,  2012, 81(3), 233-246.
[http://dx.doi.org/10.1038/ki.2011.341] [PMID: 21975860] 
[37] 
Obermayr, R.P.; Temml, C.; Knechtelsdorfer, M.; Gutjahr, G.; Kletzmayr, J.; Heiss, S.; Ponholzer, A.; Madersbacher, S.; Oberbauer, R.; Klauser-Braun, R. Predictors of new-onset decline in kidney function in a general middle-european population. Nephrol. Dial. Transplant.,  2008, 23(4), 1265-1273.
[http://dx.doi.org/10.1093/ndt/gfm790] [PMID: 18039642] 
[38] 
William, J.; Hogan, D.; Batlle, D. Predicting the development of diabetic nephropathy and its progression. Adv. Chronic Kidney Dis.,  2005, 12(2), 202-211.
[http://dx.doi.org/10.1053/j.ackd.2005.02.001] [PMID: 15822056] 
[39] 
Menon, K.; Mousa, A.; de Courten, B. Effects of supplementation with carnosine and other histidine-containing dipeptides on chronic disease risk factors and outcomes: protocol for a systematic review of randomised controlled trials. BMJ Open,  2018, 8(3) e020623
[http://dx.doi.org/10.1136/bmjopen-2017-020623] [PMID: 29567852] 
[40] 
Hasanein, P.; Felegari, Z. Chelating effects of carnosine in ameliorating nickel-induced nephrotoxicity in rats. Can. J. Physiol. Pharmacol.,  2017, 95(12), 1426-1432.
[http://dx.doi.org/10.1139/cjpp-2016-0647] [PMID: 28675793] 
[41] 
Arnal, N.; de Alaniz, M.J.; Marra, C.A. Carnosine and neocuproine as neutralizing agents for copper overload-induced damages in cultured human cells. Chem. Biol. Interact.,  2011, 192(3), 257-263.
[http://dx.doi.org/10.1016/j.cbi.2011.03.017] [PMID: 21501601] 
[42] 
Corona, C.; Frazzini, V.; Silvestri, E.; Lattanzio, R.; La Sorda, R.; Piantelli, M.; Canzoniero, L.M.; Ciavardelli, D.; Rizzarelli, E.; Sensi, S.L. Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg-AD mice. PLoS One,  2011, 6(3) e17971
[http://dx.doi.org/10.1371/journal.pone.0017971] [PMID: 21423579] 
[43] 
Aldini, G.; Orioli, M.; Rossoni, G.; Savi, F.; Braidotti, P.; Vistoli, G.; Yeum, K.J.; Negrisoli, G.; Carini, M. The carbonyl scavenger carnosine ameliorates dyslipidaemia and renal function in Zucker obese rats. J. Cell. Mol. Med.,  2011, 15(6), 1339-1354.
[http://dx.doi.org/10.1111/j.1582-4934.2010.01101.x] [PMID: 20518851] 
[44] 
Baba, S.P.; Hoetker, J.D.; Merchant, M.; Klein, J.B.; Cai, J.; Barski, O.A.; Conklin, D.J.; Bhatnagar, A. Role of aldose reductase in the metabolism and detoxification of carnosine-acrolein conjugates. J. Biol. Chem.,  2013, 288(39), 28163-28179.
[http://dx.doi.org/10.1074/jbc.M113.504753] [PMID: 23928303] 
[45] 
Tan, K.M.; Candlish, J.K. Carnosine and anserine as modulators of neutrophil function. Clin. Lab. Haematol.,  1998, 20(4), 239-244.
[http://dx.doi.org/10.1046/j.1365-2257.1998.00123.x] [PMID: 9777271] 
[46] 
Tecklenborg, J.; Clayton, D.; Siebert, S.; Coley, S.M. The role of the immune system in kidney disease. Clin. Exp. Immunol.,  2018, 192(2), 142-150.
[http://dx.doi.org/10.1111/cei.13119] [PMID: 29453850] 
[47] 
McFarland, G.A.; Holliday, R. Further evidence for the rejuvenating effects of the dipeptide L-carnosine on cultured human diploid fibroblasts. Exp. Gerontol.,  1999, 34(1), 35-45.
[http://dx.doi.org/10.1016/S0531-5565(98)00056-4] [PMID: 10197726] 
[48] 
Shao, L.; Li, Q.H.; Tan, Z. L-carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts. Biochem. Biophys. Res. Commun.,  2004, 324(2), 931-936.
[http://dx.doi.org/10.1016/j.bbrc.2004.09.136] [PMID: 15474517] 
[49] 
Pan, K.Z.; Palter, J.E.; Rogers, A.N.; Olsen, A.; Chen, D.; Lithgow, G.J.; Kapahi, P. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell,  2007, 6(1), 111-119.
[http://dx.doi.org/10.1111/j.1474-9726.2006.00266.x] [PMID: 17266680] 
[50] 
Hipkiss, A.R. Energy metabolism, proteotoxic stress and age-related dysfunction - protection by carnosine. Mol. Aspects Med.,  2011, 32(4-6), 267-278.
[http://dx.doi.org/10.1016/j.mam.2011.10.004] [PMID: 22020113] 
[51] 
Nagai, K.; Tanida, M.; Niijima, A.; Tsuruoka, N.; Kiso, Y.; Horii, Y.; Shen, J.; Okumura, N. Role of L-carnosine in the control of blood glucose, blood pressure, thermogenesis, and lipolysis by autonomic nerves in rats: involvement of the circadian clock and histamine. Amino Acids,  2012, 43(1), 97-109.
[http://dx.doi.org/10.1007/s00726-012-1251-9] [PMID: 22367578] 
[52] 
Nagai, K.; Niijima, A.; Yamano, T.; Otani, H.; Okumra, N.; Tsuruoka, N.; Nakai, M.; Kiso, Y. Possible role of L-carnosine in the regulation of blood glucose through controlling autonomic nerves. Exp. Biol. Med. (Maywood),  2003, 228(10), 1138-1145.
[http://dx.doi.org/10.1177/153537020322801007] [PMID: 14610252] 
[53] 
Fujii, T.; Kurata, H.; Takaoka, M.; Muraoka, T.; Fujisawa, Y.; Shokoji, T.; Nishiyama, A.; Abe, Y.; Matsumura, Y. The role of renal sympathetic nervous system in the pathogenesis of ischemic acute renal failure. Eur. J. Pharmacol.,  2003, 481(2-3), 241-248.
[http://dx.doi.org/10.1016/j.ejphar.2003.09.036] [PMID: 14642792] 
[54] 
Fujii, T.; Takaoka, M.; Tsuruoka, N.; Kiso, Y.; Tanaka, T.; Matsumura, Y. Dietary supplementation of L-carnosine prevents ischemia/reperfusion-induced renal injury in rats. Biol. Pharm. Bull.,  2005, 28(2), 361-363.
[http://dx.doi.org/10.1248/bpb.28.361] [PMID: 15684500] 
[55] 
Kurata, H.; Fujii, T.; Tsutsui, H.; Katayama, T.; Ohkita, M.; Takaoka, M.; Tsuruoka, N.; Kiso, Y.; Ohno, Y.; Fujisawa, Y.; Shokoji, T.; Nishiyama, A.; Abe, Y.; Matsumura, Y. Renoprotective effects of l-carnosine on ischemia/reperfusion-induced renal injury in rats. J. Pharmacol. Exp. Ther.,  2006, 319(2), 640-647.
[http://dx.doi.org/10.1124/jpet.106.110122] [PMID: 16916994] 
[56] 
Riedl, E.; Pfister, F.; Braunagel, M.; Brinkkötter, P.; Sternik, P.; Deinzer, M.; Bakker, S.J.; Henning, R.H.; van den Born, J.; Krämer, B.K.; Navis, G.; Hammes, H.P.; Yard, B.; Koeppel, H. Carnosine prevents apoptosis of glomerular cells and podocyte loss in STZ diabetic rats. Cell. Physiol. Biochem.,  2011, 28(2), 279-288.
[http://dx.doi.org/10.1159/000331740] [PMID: 21865735] 
[57] 
Hsu, H.; Hoffmann, S.; Di Marco, G.S.; Endlich, N.; Peter-Katalinić, J.; Weide, T.; Pavenstädt, H. Down-regulation of peroxiredoxin 2 contributes to angiotensin II-mediated podocyte apoptosis. Kidney Int.,  2011, 80(9), 959-969.
[http://dx.doi.org/10.1038/ki.2011.250] [PMID: 21814176] 
[58] 
Soliman, K.M.; Abdul-Hamid, M.; Othman, A.I. Effect of carnosine on gentamicin-induced nephrotoxicity. Med. Sci. Monit.,  2007, 13(3), BR73-BR83.
[PMID: 17325631] 
[59] 
Peters, V.; Jansen, E.E.; Jakobs, C.; Riedl, E.; Janssen, B.; Yard, B.A.; Wedel, J.; Hoffmann, G.F.; Zschocke, J.; Gotthardt, D.; Fischer, C.; Köppel, H. Anserine inhibits carnosine degradation but in human serum carnosinase (CN1) is not correlated with histidine dipeptide concentration. Clin. Chim. Acta,  2011, 412(3-4), 263-267.
[http://dx.doi.org/10.1016/j.cca.2010.10.016] [PMID: 20971102] 
[60] 
Ahluwalia, T.S.; Lindholm, E.; Groop, L.C. Common variants in CNDP1 and CNDP2, and risk of nephropathy in type 2 diabetes. Diabetologia,  2011, 54(9), 2295-2302.
[http://dx.doi.org/10.1007/s00125-011-2178-5] [PMID: 21573905] 
[61] 
Alkhalaf, A.; Bakker, S.J.; Bilo, H.J.; Gans, R.O.; Navis, G.J.; Postmus, D.; Forsblom, C.; Groop, P.H.; Vionnet, N.; Hadjadj, S.; Marre, M.; Parving, H.H.; Rossing, P.; Tarnow, L. A polymorphism in the gene encoding carnosinase (CNDP1) as a predictor of mortality and progression from nephropathy to end-stage renal disease in type 1 diabetes mellitus. Diabetologia,  2010, 53(12), 2562-2568.
[http://dx.doi.org/10.1007/s00125-010-1863-0] [PMID: 20711718] 
[62] 
Janssen, B.; Hohenadel, D.; Brinkkoetter, P.; Peters, V.; Rind, N.; Fischer, C.; Rychlik, I.; Cerna, M.; Romzova, M.; de Heer, E.; Baelde, H.; Bakker, S.J.; Zirie, M.; Rondeau, E.; Mathieson, P.; Saleem, M.A.; Meyer, J.; Köppel, H.; Sauerhoefer, S.; Bartram, C.R.; Nawroth, P.; Hammes, H.P.; Yard, B.A.; Zschocke, J.; van der Woude, F.J. Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1. Diabetes,  2005, 54(8), 2320-2327.
[http://dx.doi.org/10.2337/diabetes.54.8.2320] [PMID: 16046297] 
[63] 
Peters, V.; Zschocke, J.; Schmitt, C.P. Carnosinase, diabetes mellitus and the potential relevance of carnosinase deficiency. J. Inherit. Metab. Dis.,  2018, 41(1), 39-47.
[http://dx.doi.org/10.1007/s10545-017-0099-2] [PMID: 29027595] 
[64] 
Freedman, B.I.; Hicks, P.J.; Sale, M.M.; Pierson, E.D.; Langefeld, C.D.; Rich, S.S.; Xu, J.; McDonough, C.; Janssen, B.; Yard, B.A.; van der Woude, F.J.; Bowden, D.W. A leucine repeat in the carnosinase gene CNDP1 is associated with diabetic end-stage renal disease in European Americans. Nephrol. Dial. Transplant.,  2007, 22(4), 1131-1135.
[http://dx.doi.org/10.1093/ndt/gfl717] [PMID: 17205963] 
[65] 
Yadav, A.K.; Sinha, N.; Kumar, V.; Bhansali, A.; Dutta, P.; Jha, V. Association of CTG repeat polymorphism in carnosine dipeptidase 1 (CNDP1) gene with diabetic nephropathy in north Indians. Indian J. Med. Res.,  2016, 144(1), 32-37.
[http://dx.doi.org/10.4103/0971-5916.193280] [PMID: 27834323] 
[66] 
Wanic, K.; Placha, G.; Dunn, J.; Smiles, A.; Warram, J.H.; Krolewski, A.S. Exclusion of polymorphisms in carnosinase genes (CNDP1 and CNDP2) as a cause of diabetic nephropathy in type 1 diabetes: results of large case-control and follow-up studies. Diabetes,  2008, 57(9), 2547-2551.
[http://dx.doi.org/10.2337/db08-1303] [PMID: 18753673] 
[67] 
McDonough, C.W.; Hicks, P.J.; Lu, L.; Langefeld, C.D.; Freedman, B.I.; Bowden, D.W. The influence of carnosinase gene polymorphisms on diabetic nephropathy risk in African-Americans. Hum. Genet.,  2009, 126(2), 265-275.
[http://dx.doi.org/10.1007/s00439-009-0667-0] [PMID: 19373489] 
[68] 
Alkhalaf, A.; Landman, G.W.; van Hateren, K.J.; Groenier, K.H.; Mooyaart, A.L.; De Heer, E.; Gans, R.O.; Navis, G.J.; Bakker, S.J.; Kleefstra, N.; Bilo, H.J. Sex specific association between carnosinase gene CNDP1 and cardiovascular mortality in patients with type 2 diabetes (ZODIAC-22). J. Nephrol.,  2015, 28(2), 201-207.
[http://dx.doi.org/10.1007/s40620-014-0096-6] [PMID: 24756973] 
[69] 
Mooyaart, A.L.; Zutinic, A.; Bakker, S.J.; Grootendorst, D.C.; Kleefstra, N.; van Valkengoed, I.G.; Böhringer, S.; Bilo, H.J.; Dekker, F.W.; Bruijn, J.A.; Navis, G.; Janssen, B.; Baelde, H.J.; De Heer, E. Association between CNDP1 genotype and diabetic nephropathy is sex specific. Diabetes,  2010, 59(6), 1555-1559.
[http://dx.doi.org/10.2337/db09-1377] [PMID: 20332346] 
[70] 
Kiliś-Pstrusińska, K.; Zwolińska, D.; Grzeszczak, W. Is carnosinase 1 gene (CNDP1) polymorphism associated with chronic kidney disease progression in children and young adults? results of a family-based study. Arch. Med. Res.,  2010, 41(5), 356-362.
[http://dx.doi.org/10.1016/j.arcmed.2010.07.006] [PMID: 20851293] 
[71] 
Riedl, E.; Koeppel, H.; Brinkkoetter, P.; Sternik, P.; Steinbeisser, H.; Sauerhoefer, S.; Janssen, B.; van der Woude, F.J.; Yard, B.A. A CTG polymorphism in the CNDP1 gene determines the secretion of serum carnosinase in Cos-7 transfected cells. Diabetes,  2007, 56(9), 2410-2413.
[http://dx.doi.org/10.2337/db07-0128] [PMID: 17601991] 
[72] 
Perry, T.L.; Hansen, S.; Love, D.L. Serum-carnosinase deficiency in carnosinaemia. Lancet,  1968, 1(7554), 1229-1230.
[http://dx.doi.org/10.1016/S0140-6736(68)91924-7] [PMID: 4172777] 
[73] 
Peters, V.; Lanthaler, B.; Amberger, A.; Fleming, T.; Forsberg, E.; Hecker, M.; Wagner, A.H.; Yue, W.W.; Hoffmann, G.F.; Nawroth, P.; Zschocke, J.; Schmitt, C.P. Carnosine metabolism in diabetes is altered by reactive metabolites. Amino Acids,  2015, 47(11), 2367-2376.
[http://dx.doi.org/10.1007/s00726-015-2024-z] [PMID: 26081982] 
[74] 
Peters, V.; Schmitt, C.P.; Weigand, T.; Klingbeil, K.; Thiel, C.; van den Berg, A.; Calabrese, V.; Nawroth, P.; Fleming, T.; Forsberg, E.; Wagner, A.H.; Hecker, M.; Vistoli, G. Allosteric inhibition of carnosinase (CN1) by inducing a conformational shift. J. Enzyme Inhib. Med. Chem.,  2017, 32(1), 1102-1110.
[http://dx.doi.org/10.1080/14756366.2017.1355793] [PMID: 28776438] 
[75] 
Vanholder, R.; Cornelis, R.; Dhondt, A.; Lameire, N. The role of trace elements in uraemic toxicity. Nephrol. Dial. Transplant.,  2002, 17(Suppl. 2), 2-8.
[http://dx.doi.org/10.1093/ndt/17.suppl_2.2] [PMID: 11904350] 
[76] 
Chakkera, H.A.; Hanson, R.L.; Kobes, S.; Millis, M.P.; Nelson, R.G.; Knowler, W.C.; Distefano, J.K. Association of variants in the carnosine peptidase 1 gene (CNDP1) with diabetic nephropathy in American Indians. Mol. Genet. Metab.,  2011, 103(2), 185-190.
[http://dx.doi.org/10.1016/j.ymgme.2011.02.010] [PMID: 21393041] 
[77] 
Yay, A.; Akkuş, D.; Yapıslar, H.; Balcıoglu, E.; Sonmez, M.F.; Ozdamar, S. Antioxidant effect of carnosine treatment on renal oxidative stress in streptozotocin-induced diabetic rats. Biotech. Histochem.,  2014, 89(8), 552-557.
[http://dx.doi.org/10.3109/10520295.2014.913811] [PMID: 24834928] 
[78] 
Jessen, H. Taurine and beta-alanine transport in an established human kidney cell line derived from the proximal tubule. Biochim. Biophys. Acta,  1994, 1194(1), 44-52.
[http://dx.doi.org/10.1016/0005-2736(94)90201-1] [PMID: 8075140] 
[79] 
Basile, D.P.; Anderson, M.D.; Sutton, T.A. Pathophysiology of acute kidney injury. Compr. Physiol.,  2012, 2(2), 1303-1353.
[PMID: 23798302] 
[80] 
Fujii, T.; Takaoka, M.; Tsuruoka, N.; Kiso, Y.; Tanaka, T.; Matsumura, Y.; Matsumura, Y. Dietary supplementation of L-carnosine prevents ischemia/reperfusion-induced renal injury in rats. Biol. Pharm. Bull.,  2005, 28(2), 361-363.
[http://dx.doi.org/10.1248/bpb.28.361] [PMID: 15684500] 
[81] 
Sahin, S.; Burukoglu Donmez, D. Effects of carnosine (beta-alanyl-L-histidine) in an experimental rat model of acute kidney injury due to septic shock. Med. Sci. Monit.,  2018, 24, 305-316.
[http://dx.doi.org/10.12659/MSM.905181] [PMID: 29334583] 
[82] 
Noori, S.; Mahboob, T. Antioxidant effect of carnosine pretreatment on cisplatin-induced renal oxidative stress in rats. Indian J. Clin. Biochem.,  2010, 25(1), 86-91.
[http://dx.doi.org/10.1007/s12291-010-0018-x] [PMID: 23105891] 
[83] 
Kumral, A.; Giriş, M.; Soluk-Tekkeşin, M.; Olgaç, V.; Doğru-Abbasoğlu, S.; Türkoğlu, Ü.; Uysal, M. Beneficial effects of carnosine and carnosine plus vitamin E treatments on doxorubicin-induced oxidative stress and cardiac, hepatic, and renal toxicity in rats. Hum. Exp. Toxicol.,  2016, 35(6), 635-643.
[http://dx.doi.org/10.1177/0960327115597468] [PMID: 26224044] 
[84] 
Sauerhöfer, S.; Yuan, G.; Braun, G.S.; Deinzer, M.; Neumaier, M.; Gretz, N.; Floege, J.; Kriz, W.; van der Woude, F.; Moeller, M.J. L-carnosine, a substrate of carnosinase-1, influences glucose metabolism. Diabetes,  2007, 56(10), 2425-2432.
[http://dx.doi.org/10.2337/db07-0177] [PMID: 17601992] 
[85] 
Gualano, B.; Everaert, I.; Stegen, S.; Artioli, G.G.; Taes, Y.; Roschel, H.; Achten, E.; Otaduy, M.C.; Junior, A.H.; Harris, R.; Derave, W. Reduced muscle carnosine content in type 2, but not in type 1 diabetic patients. Amino Acids,  2012, 43(1), 21-24.
[http://dx.doi.org/10.1007/s00726-011-1165-y] [PMID: 22120670] 
[86] 
Bispo, V.S.; de Arruda Campos, I.P.; Di Mascio, P.; Medeiros, M.H. Structural elucidation of a carnosine-acrolein adduct and its quantification in human urine samples. Sci. Rep.,  2016, 6, 19348.
[http://dx.doi.org/10.1038/srep19348] [PMID: 26783107] 
[87] 
Albrecht, T.; Schilperoort, M.; Zhang, S.; Braun, J.D.; Qiu, J.; Rodriguez, A.; Pastene, D.O.; Krämer, B.K.; Köppel, H.; Baelde, H.; de Heer, E.; Anna Altomare, A.; Regazzoni, L.; Denisi, A.; Aldini, G.; van den Born, J.; Yard, B.A.; Hauske, S.J. Carnosine attenuates the development of both type 2 diabetes and diabetic nephropathy in BTBR ob/ob Mice. Sci. Rep.,  2017, 7, 44492.
[http://dx.doi.org/10.1038/srep44492] [PMID: 28281693] 
[88] 
Mooyaart, A.L.; van Valkengoed, I.G.; Shaw, P.K.; Peters, V.; Baelde, H.J.; Rabelink, T.J.; Bruijn, J.A.; Stronks, K.; de Heer, E. Lower frequency of the 5/5 homozygous CNDP1 genotype in South Asian Surinamese. Diabetes Res. Clin. Pract.,  2009, 85(3), 272-278.
[http://dx.doi.org/10.1016/j.diabres.2009.06.001] [PMID: 19577318] 
[89] 
Kurashige, M.; Imamura, M.; Araki, S.; Suzuki, D.; Babazono, T.; Uzu, T.; Umezono, T.; Toyoda, M.; Kawai, K.; Imanishi, M.; Hanaoka, K.; Maegawa, H.; Uchigata, Y.; Hosoya, T.; Maeda, S. The influence of a single nucleotide polymorphism within CNDP1 on susceptibility to diabetic nephropathy in Japanese women with type 2 diabetes. PLoS One,  2013, 8(1) e54064
[http://dx.doi.org/10.1371/journal.pone.0054064] [PMID: 23342076] 
[90] 
Craig, D.W.; Millis, M.P.; DiStefano, J.K. Genome-wide SNP genotyping study using pooled DNA to identify candidate markers mediating susceptibility to end-stage renal disease attributed to Type 1 diabetes. Diabet. Med.,  2009, 26(11), 1090-1098.
[http://dx.doi.org/10.1111/j.1464-5491.2009.02846.x] [PMID: 19929986] 
[91] 
Albrecht, T.; Zhang, S.; Braun, J.D.; Xia, L.; Rodriquez, A.; Qiu, J.; Peters, V.; Schmitt, C.P.; van den Born, J.; Bakker, S.J.L.; Lammert, A.; Köppel, H.; Schnuelle, P.; Krämer, B.K.; Yard, B.A.; Hauske, S.J. The CNDP1 (CTG)5 polymorphism is associated with biopsy-proven diabetic nephropathy, time on hemodialysis, and diabetes duration. J. Diabetes Res.,  2017, 2017 9506730
[http://dx.doi.org/10.1155/2017/9506730] [PMID: 28553654] 
[92] 
Willi, S.M.; Zhang, Y.; Hill, J.B.; Phelan, M.C.; Michaelis, R.C.; Holden, K.R. A deletion in the long arm of chromosome 18 in a child with serum carnosinase deficiency. Pediatr. Res.,  1997, 41(2), 210-213.
[http://dx.doi.org/10.1203/00006450-199702000-00009] [PMID: 9029640] 
[93] 
Niijima, A.; Okui, T.; Matsumura, Y.; Yamano, T.; Tsuruoka, N.; Kiso, Y.; Nagai, K. Effects of L-carnosine on renal sympathetic nerve activity and DOCA-salt hypertension in rats. Auton. Neurosci.,  2002, 97(2), 99-102.
[http://dx.doi.org/10.1016/S1566-0702(02)00048-6] [PMID: 12132650] 
[94] 
Tanida, M.; Niijima, A.; Fukuda, Y.; Sawai, H.; Tsuruoka, N.; Shen, J.; Yamada, S.; Kiso, Y.; Nagai, K. Dose-dependent effects of L-carnosine on the renal sympathetic nerve and blood pressure in urethane-anesthetized rats. Am. J. Physiol. Regul. Integr. Comp. Physiol.,  2005, 288(2), R447-R455.
[http://dx.doi.org/10.1152/ajpregu.00275.2004] [PMID: 15498968] 
[95] 
Tanida, M.; Kaneko, H.; Shen, J.; Nagai, K. Involvement of the histaminergic system in renal sympathetic and cardiovascular responses to leptin and ghrelin. Neurosci. Lett.,  2007, 413(1), 88-92.
[http://dx.doi.org/10.1016/j.neulet.2006.11.035] [PMID: 17166664] 
[96] 
Brown, B.E.; Kim, C.H.; Torpy, F.R.; Bursill, C.A.; McRobb, L.S.; Heather, A.K.; Davies, M.J.; van Reyk, D.M. Supplementation with carnosine decreases plasma triglycerides and modulates atherosclerotic plaque composition in diabetic apo E(-/-) mice. Atherosclerosis,  2014, 232(2), 403-409.
[http://dx.doi.org/10.1016/j.atherosclerosis.2013.11.068] [PMID: 24468155] 
[97] 
Snyder, S.; Turner, G.A.; Turner, A. Obesity-related kidney disease. Prim. Care,  2014, 41(4), 875-893.
[http://dx.doi.org/10.1016/j.pop.2014.08.008] [PMID: 25439539] 
[98] 
Kovesdy, C.P.; Furth, S.L.; Zoccali, C. Obesity and kidney disease: Hidden consequences of the epidemic. Afr. J. Prim. Health Care Fam. Med.,  2017, 9(1), e1-e3.
[http://dx.doi.org/10.4102/phcfm.v9i1.1435] [PMID: 29113441] 
[99] 
Park, J.; Ahmadi, S.F.; Streja, E.; Molnar, M.Z.; Flegal, K.M.; Gillen, D.; Kovesdy, C.P.; Kalantar-Zadeh, K. Obesity paradox in end-stage kidney disease patients. Prog. Cardiovasc. Dis.,  2014, 56(4), 415-425.
[http://dx.doi.org/10.1016/j.pcad.2013.10.005] [PMID: 24438733] 
[100] 
Wang, Y.; Chen, X.; Song, Y.; Caballero, B.; Cheskin, L.J. Association between obesity and kidney disease: a systematic review and meta-analysis. Kidney Int.,  2008, 73(1), 19-33.
[http://dx.doi.org/10.1038/sj.ki.5002586] [PMID: 17928825] 
[101] 
Sauerhöfer, S.; Yuan, G.; Braun, G.S.; Deinzer, M.; Neumaier, M.; Gretz, N.; Floege, J.; Kriz, W.; van der Woude, F.; Moeller, M.J. L-carnosine, a substrate of carnosinase-1, influences glucose metabolism. Diabetes,  2007, 56(10), 2425-2432.
[http://dx.doi.org/10.2337/db07-0177] [PMID: 17601992] 
[102] 
Lee, Y.T.; Hsu, C.C.; Lin, M.H.; Liu, K.S.; Yin, M.C. Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur. J. Pharmacol.,  2005, 513(1-2), 145-150.
[http://dx.doi.org/10.1016/j.ejphar.2005.02.010] [PMID: 15878720] 
[103] 
de Courten, B.; Jakubova, M.; de Courten, M.P.; Kukurova, I.J.; Vallova, S.; Krumpolec, P.; Valkovic, L.; Kurdiova, T.; Garzon, D.; Barbaresi, S.; Teede, H.J.; Derave, W.; Krssak, M.; Aldini, G.; Ukropec, J.; Ukropcova, B. Effects of carnosine supplementation on glucose metabolism: Pilot clinical trial. Obesity (Silver Spring),  2016, 24(5), 1027-1034.
[http://dx.doi.org/10.1002/oby.21434] [PMID: 27040154] 
[104] 
Liu, Y.; Cotillard, A.; Vatier, C.; Bastard, J.P.; Fellahi, S.; Stévant, M.; Allatif, O.; Langlois, C.; Bieuvelet, S.; Brochot, A.; Guilbot, A.; Clément, K.; Rizkalla, S.W. A Dietary supplement containing cinnamon, chromium and carnosine decreases fasting plasma glucose and increases lean mass in overweight or obese pre- diabetic subjects: a randomized, placebo-controlled trial. PLoS One,  2015, 10(9) e0138646
[http://dx.doi.org/10.1371/journal.pone.0138646] [PMID: 26406981] 
[105] 
Regazzoni, L.; de Courten, B.; Garzon, D.; Altomare, A.; Marinello, C.; Jakubova, M.; Vallova, S.; Krumpolec, P.; Carini, M.; Ukropec, J.; Ukropcova, B.; Aldini, G. A carnosine intervention study in overweight human volunteers: bioavailability and reactive carbonyl species sequestering effect. Sci. Rep.,  2016, 6, 27224.
[http://dx.doi.org/10.1038/srep27224] [PMID: 27265207] 
[106] 
Sanchez-Niño, M.D.; Sanz, A.B.; Ramos, A.M.; Ruiz-Ortega, M.; Ortiz, A. Translational science in chronic kidney disease. Clin. Sci. ,  2017, 131(14), 1617-1629.
[http://dx.doi.org/10.1042/CS20160395] 
[107] 
Baye, E.; Menon, K.; de Courten, M.P.; Earnest, A.; Cameron, J.; de Courten, B. Does supplementation with carnosine improve cardiometabolic health and cognitive function in patients with pre-diabetes and type 2 diabetes? study protocol for a randomised, double-blind, placebo-controlled trial. BMJ Open,  2017, 7(9) e017691
[http://dx.doi.org/10.1136/bmjopen-2017-017691] [PMID: 28864708] 
[108] 
de Courten, B.; Kurdiova, T.; de Courten, M.P.; Belan, V.; Everaert, I.; Vician, M.; Teede, H.; Gasperikova, D.; Aldini, G.; Derave, W.; Ukropec, J.; Ukropcova, B. Muscle carnosine is associated with cardiometabolic risk factors in humans. PLoS One,  2015, 10(10) e0138707
[http://dx.doi.org/10.1371/journal.pone.0138707] [PMID: 26439389] 
[109] 
Komers, R.; Plotkin, H. Dual inhibition of renin-angiotensin-aldosterone system and endothelin-1 in treatment of chronic kidney disease. Am. J. Physiol. Regul. Integr. Comp. Physiol.,  2016, 310(10), R877-R884.
[http://dx.doi.org/10.1152/ajpregu.00425.2015] [PMID: 27009050] 
[110] 
Chan, S. Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. Br. J. Cancer,  2004, 91(8), 1420-1424.
[http://dx.doi.org/10.1038/sj.bjc.6602162] [PMID: 15365568] 
[111] 
Laplante, M.; Sabatini, D.M. mTOR signaling in growth control and disease. Cell,  2012, 149(2), 274-293.
[http://dx.doi.org/10.1016/j.cell.2012.03.017] [PMID: 22500797] 
[112] 
Zhang, Z.; Miao, L.; Wu, X.; Liu, G.; Peng, Y.; Xin, X.; Jiao, B.; Kong, X. Carnosine inhibits the proliferation of human gastric carcinoma cells by retarding Akt/mTOR/p70S6K signaling. J. Cancer,  2014, 5(5), 382-389.
[http://dx.doi.org/10.7150/jca.8024] [PMID: 24799956] 
[113] 
Everaert, I.; Taes, Y.; De Heer, E.; Baelde, H.; Zutinic, A.; Yard, B.; Sauerhöfer, S.; Vanhee, L.; Delanghe, J.; Aldini, G.; Derave, W. Low plasma carnosinase activity promotes carnosinemia after carnosine ingestion in humans. Am. J. Physiol. Renal Physiol.,  2012, 302(12), F1537-F1544.
[http://dx.doi.org/10.1152/ajprenal.00084.2012] [PMID: 22496410] 
[114] 
Mooyaart, A.L. Genetic associations in diabetic nephropathy. Clin. Exp. Nephrol.,  2014, 18(2), 197-200.
[http://dx.doi.org/10.1007/s10157-013-0874-9] [PMID: 24129556] 
[115] 
Peters, V.; Kebbewar, M.; Janssen, B.; Hoffmann, G.F.; Möller, K.; Wygoda, S.; Charbit, M.; Fernandes-Teixeira, A.; Jeck, N.; Zschocke, J.; Schmitt, C.P.; Schäfer, F.; Wühl, E. CNDP1 genotype and renal survival in pediatric nephropathies. J. Pediatr. Endocrinol. Metab.,  2016, 29(7), 827-833.
[http://dx.doi.org/10.1515/jpem-2015-0262] [PMID: 27278783] 
[116] 
Qiu, J.; Hauske, S.J.; Zhang, S.; Rodriguez-Niño, A.; Albrecht, T.; Pastene, D.O.; van den Born, J.; van Goor, H.; Ruf, S.; Kohlmann, M.; Teufel, M.; Krämer, B.K.; Hammes, H.P.; Peters, V.; Yard, B.A.; Kannt, A. Identification and characterisation of carnostatine (SAN9812), a potent and selective carnosinase (CN1) inhibitor with in vivo activity. Amino Acids, 2018.
[http://dx.doi.org/10.1007/s00726-018-2601-z] [PMID: 29922921] 
Rights & Permissions Print Cite
Article Metrics
44
3
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0929867326666190730130024	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
Current Medicinal Chemistry

Carnosine and Kidney Diseases: What We Currently Know?

Abstract Play Pause

Related Journals

Related Books

Related Articles

Abstract
