Carnosine and Diabetic Nephropathy

Author(s): Verena Peters*, Benito Yard, Claus Peter Schmitt

Journal Name: Current Medicinal Chemistry

Volume 27 , Issue 11 , 2020


DOI : 10.2174/0929867326666190326111851

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor

Abstract:

Diabetic Nephropathy (DN) is a major complication in patients with type 1 or type 2 diabetes and represents the leading cause of end-stage renal disease. Novel therapeutic approaches are warranted. In view of a polymorphism in the carnosinase 1 gene CNDP1, resulting in reduced carnosine degradation activity and a significant DN risk reduction, carnosine (β-alanyl-L-histidine) has gained attention as a potential therapeutic target. Carnosine has anti-inflammatory, antioxidant, anti-glycation and reactive carbonyl quenching properties. In diabetic rodents, carnosine supplementation consistently improved renal histology and function and in most studies, also glucose metabolism. Even though plasma half-life of carnosine in humans is short, first intervention studies in (pre-) diabetic patients yielded promising results. The precise molecular mechanisms of carnosine mediated protective action, however, are still incompletely understood. This review highlights the recent knowledge on the role of the carnosine metabolism in DN.

Keywords: CNDP1 gene, Carnosine, diabetic nephropathy, end-stage renal disease, histidine-containing dipeptides, polymorphism.

[1]
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]
[2]
Kwiatkowski, S.; Kiersztan, A.; Drozak, J. Biosynthesis of carnosine and related dipeptides in vertebrates. Curr. Protein Pept. Sci., 2018, 19(8), 771-789.
[http://dx.doi.org/10.2174/1389203719666180226155657] [PMID: 29484990]
[3]
Babizhayev, M.A. Current ocular drug delivery challenges for N-acetylcarnosine: novel patented routes and modes of delivery, design for enhancement of therapeutic activity and drug delivery relationships. Recent Pat. Drug Deliv. Formul., 2009, 3(3), 229-265.
[http://dx.doi.org/10.2174/187221109789105621] [PMID: 19534670]
[4]
Kawahara, M.; Tanaka, K.I.; Kato-Negishi, M. Zinc, carnosine, and neurodegenerative diseases. Nutrients, 2018, 10(2)E147
[http://dx.doi.org/10.3390/nu10020147] [PMID: 29382141]
[5]
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]
[6]
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]
[7]
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]
[8]
Barca, A.; Gatti, F.; Spagnolo, D.; Ippati, S.; Vetrugno, C.; Verri, T. Responsiveness of carnosine homeostasis genes in the pancreas and brain of streptozotocin-treated mice exposed to dietary carnosine. Int. J. Mol. Sci., 2018, 19(6), 19.
[http://dx.doi.org/10.3390/ijms19061713] [PMID: 29890740]
[9]
Pfister, F.; Riedl, E.; Wang, Q.; vom Hagen, F.; Deinzer, M.; Harmsen, M.C.; Molema, G.; Yard, B.; Feng, Y.; Hammes, H.P. Oral carnosine supplementation prevents vascular damage in experimental diabetic retinopathy. Cell. Physiol. Biochem., 2011, 28(1), 125-136.
[http://dx.doi.org/10.1159/000331721] [PMID: 21865855]
[10]
Mong, M.C.; Chao, C.Y.; Yin, M.C. Histidine and carnosine alleviated hepatic steatosis in mice consumed high saturated fat diet. Eur. J. Pharmacol., 2011, 653(1-3), 82-88.
[http://dx.doi.org/10.1016/j.ejphar.2010.12.001] [PMID: 21167151]
[11]
Kamal, M.A.; Jiang, H.; Hu, Y.; Keep, R.F.; Smith, D.E. Influence of genetic knockout of Pept2 on the in vivo disposition of endogenous and exogenous carnosine in wild-type and Pept2 null mice. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2009, 296(4), R986-R991.
[http://dx.doi.org/10.1152/ajpregu.90744.2008] [PMID: 19225147]
[12]
Barski, O.A.; Xie, Z.; Baba, S.P.; Sithu, S.D.; Agarwal, A.; Cai, J.; Bhatnagar, A.; Srivastava, S. Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein E-null mice. Arterioscler. Thromb. Vasc. Biol., 2013, 33(6), 1162-1170.
[http://dx.doi.org/10.1161/ATVBAHA.112.300572] [PMID: 23559625]
[13]
Negre-Salvayre, A.; Coatrieux, C.; Ingueneau, C.; Salvayre, R. Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors. Br. J. Pharmacol., 2008, 153(1), 6-20.
[http://dx.doi.org/10.1038/sj.bjp.0707395] [PMID: 17643134]
[14]
Vistoli, G.; Orioli, M.; Pedretti, A.; Regazzoni, L.; Canevotti, R.; Negrisoli, G.; Carini, M.; Aldini, G. Design, synthesis, and evaluation of carnosine derivatives as selective and efficient sequestering agents of cytotoxic reactive carbonyl species. ChemMedChem, 2009, 4(6), 967-975.
[http://dx.doi.org/10.1002/cmdc.200800433] [PMID: 19301317]
[15]
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]
[16]
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]
[17]
Nakagawa, K.; Ueno, A.; Nishikawa, Y. Interactions between carnosine and captopril on free radical scavenging activity and angiotensin-converting enzyme activity in vitro. Yakugaku Zasshi, 2006, 126(1), 37-42.
[http://dx.doi.org/10.1248/yakushi.126.37] [PMID: 16394648]
[18]
Weigand, T.; Singler, B.; Fleming, T.; Nawroth, P.; Klika, K.D.; Thiel, C.; Baelde, H.; Garbade, S.F.; Wagner, A.H.; Hecker, M.; Yard, B.A.; Amberger, A.; Zschocke, J.; Schmitt, C.P.; Peters, V. Carnosine catalyzes the formation of the oligo/polymeric products of methylglyoxal. Cell. Physiol. Biochem., 2018, 46(2), 713-726.
[http://dx.doi.org/10.1159/000488727] [PMID: 29621776]
[19]
Vistoli, G.; Colzani, M.; Mazzolari, A.; Gilardoni, E.; Rivaletto, C.; Carini, M.; Aldini, G. Quenching activity of carnosine derivatives towards reactive carbonyl species: Focus on α-(methylglyoxal) and β-(malondialdehyde) dicarbonyls. Biochem. Biophys. Res. Commun., 2017, 492(3), 487-492.
[http://dx.doi.org/10.1016/j.bbrc.2017.08.069] [PMID: 28834691]
[20]
Brings, S.; Fleming, T.; De Buhr, S.; Beijer, B.; Lindner, T.; Wischnjow, A.; Kender, Z.; Peters, V.; Kopf, S.; Haberkorn, U.; Mier, W.; Nawroth, P.P. A scavenger peptide prevents methylglyoxal induced pain in mice. Biochim. Biophys. Acta Mol. Basis Dis., 2017, 1863(3), 654-662.
[http://dx.doi.org/10.1016/j.bbadis.2016.12.001] [PMID: 27932057]
[21]
Babizhayev, M.A.; Lankin, V.Z.; Savel’Yeva, E.L.; Deyev, A.I.; Yegorov, Y.E. Diabetes mellitus: novel insights, analysis and interpretation of pathophysiology and complications management with imidazole-containing peptidomimetic antioxidants. Recent Pat. Drug Deliv. Formul., 2013, 7(3), 216-256.
[http://dx.doi.org/10.2174/1872211307666131117121058] [PMID: 24236935]
[22]
Decker, E.A.; Livisay, S.A.; Zhou, S. A re-evaluation of the antioxidant activity of purified carnosine. Biochemistry (Mosc.), 2000, 65(7), 766-770.
[PMID: 10951093]
[23]
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]
[24]
Mozdzan, M.; Szemraj, J.; Rysz, J.; Nowak, D. Antioxidant properties of carnosine re-evaluated with oxidizing systems involving iron and copper ions. Basic Clin. Pharmacol. Toxicol., 2005, 96(5), 352-360.
[http://dx.doi.org/10.1111/j.1742-7843.2005.pto_03.x] [PMID: 15853927]
[25]
Velez, S.; Nair, N.G.; Reddy, V.P. Transition metal ion binding studies of carnosine and histidine: biologically relevant antioxidants. Colloids Surf. B Biointerfaces, 2008, 66(2), 291-294.
[http://dx.doi.org/10.1016/j.colsurfb.2008.06.012] [PMID: 18675540]
[26]
Grasso, G.I.; Arena, G.; Bellia, F.; Rizzarelli, E.; Vecchio, G. Copper(II)-chelating homocarnosine glycoconjugate as a new multifunctional compound. J. Inorg. Biochem., 2014, 131, 56-63.
[http://dx.doi.org/10.1016/j.jinorgbio.2013.10.020] [PMID: 24246303]
[27]
Babizhayev, M.A.; Deyev, A.I.; Yermakova, V.N.; Brikman, I.V.; Bours, J. Lipid peroxidation and cataracts: N-acetylcarnosine as a therapeutic tool to manage age-related cataracts in human and in canine eyes. Drugs R D., 2004, 5(3), 125-139.
[http://dx.doi.org/10.2165/00126839-200405030-00001] [PMID: 15139774]
[28]
Dubois, V.D.; Bastawrous, A. N-acetylcarnosine (NAC) drops for age-related cataract. Cochrane Database Syst. Rev., 2017, 2CD009493
[PMID: 28245346]
[29]
Aldini, G.; Carini, M.; Beretta, G.; Bradamante, S.; Facino, R.M. Carnosine is a quencher of 4-hydroxy-nonenal: through what mechanism of reaction? Biochem. Biophys. Res. Commun., 2002, 298(5), 699-706.
[http://dx.doi.org/10.1016/S0006-291X(02)02545-7] [PMID: 12419310]
[30]
Torreggiani, A.; Taddei, P.; Fini, G. Characterization of dioxygenated cobalt(II)-carnosine complexes by Raman and IR spectroscopy. Biopolymers, 2002, 67(1), 70-81.
[http://dx.doi.org/10.1002/bip.10025] [PMID: 11842416]
[31]
Ganguly, K.; Schinder, A.F.; Wong, S.T.; Poo, M. GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition. Cell, 2001, 105(4), 521-532.
[http://dx.doi.org/10.1016/S0092-8674(01)00341-5] [PMID: 11371348]
[32]
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]
[33]
Veiga-da-Cunha, M.; Chevalier, N.; Stroobant, V.; Vertommen, D.; Van Schaftingen, E. Metabolite proofreading in carnosine and homocarnosine synthesis: molecular identification of PM20D2 as β-alanyl-lysine dipeptidase. J. Biol. Chem., 2014, 289(28), 19726-19736.
[http://dx.doi.org/10.1074/jbc.M114.576579] [PMID: 24891507]
[34]
Drozak, J.; Chrobok, L.; Poleszak, O.; Jagielski, A.K.; Derlacz, R. Molecular identification of carnosine N-methyltransferase as chicken histamine N-methyltransferase-like protein (hnmt-like). PLoS One, 2013, 8(5)e64805
[http://dx.doi.org/10.1371/journal.pone.0064805] [PMID: 23705015]
[35]
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]
[36]
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]
[37]
Riedl, E.; Koeppel, H.; Pfister, F.; Peters, V.; Sauerhoefer, S.; Sternik, P.; Brinkkoetter, P.; Zentgraf, H.; Navis, G.; Henning, R.H.; Van Den Born, J.; Bakker, S.J.; Janssen, B.; van der Woude, F.J.; Yard, B.A. N-glycosylation of carnosinase influences protein secretion and enzyme activity: implications for hyperglycemia. Diabetes, 2010, 59(8), 1984-1990.
[http://dx.doi.org/10.2337/db09-0868] [PMID: 20460427]
[38]
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]
[39]
Bando, K.; Shimotsuji, T.; Toyoshima, H.; Hayashi, C.; Miyai, K. Fluorometric assay of human serum carnosinase activity in normal children, adults and patients with myopathy. Ann. Clin. Biochem., 1984, 21(Pt 6), 510-514.
[http://dx.doi.org/10.1177/000456328402100613] [PMID: 6517492]
[40]
Adelmann, K.; Frey, D.; Riedl, E.; Koeppel, H.; Pfister, F.; Peters, V.; Schmitt, C.P.; Sternik, P.; Hofmann, S.; Zentgraf, H.W.; Navis, G.; van den Born, J.; Bakker, S.J.; Krämer, B.K.; Yard, B.A.; Hauske, S.J. Different conformational forms of serum carnosinase detected by a newly developed sandwich ELISA for the measurements of carnosinase concentrations. Amino Acids, 2012, 43(1), 143-151.
[http://dx.doi.org/10.1007/s00726-012-1244-8] [PMID: 22349764]
[41]
Peters, V.; Kebbewar, M.; Jansen, E.W.; Jakobs, C.; Riedl, E.; Koeppel, H.; Frey, D.; Adelmann, K.; Klingbeil, K.; Mack, M.; Hoffmann, G.F.; Janssen, B.; Zschocke, J.; Yard, B.A. Relevance of allosteric conformations and homocarnosine concentration on carnosinase activity. Amino Acids, 2010, 38(5), 1607-1615.
[http://dx.doi.org/10.1007/s00726-009-0367-z] [PMID: 19915793]
[42]
Pavlin, M.; Rossetti, G.; De Vivo, M.; Carloni, P. Carnosine and homocarnosine degradation mechanisms by the human carnosinase enzyme CN1: insights from multiscale simulations. Biochemistry, 2016, 55(19), 2772-2784.
[http://dx.doi.org/10.1021/acs.biochem.5b01263] [PMID: 27105448]
[43]
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]
[44]
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]
[45]
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]
[46]
Jappar, D.; Hu, Y.; Keep, R.F.; Smith, D.E. Transport mechanisms of carnosine in SKPT cells: contribution of apical and basolateral membrane transporters. Pharm. Res., 2009, 26(1), 172-181.
[http://dx.doi.org/10.1007/s11095-008-9726-9] [PMID: 18820998]
[47]
Tuttle, K.R.; Bakris, G.L.; Bilous, R.W.; Chiang, J.L.; de Boer, I.H.; Goldstein-Fuchs, J.; Hirsch, I.B.; Kalantar-Zadeh, K.; Narva, A.S.; Navaneethan, S.D.; Neumiller, J.J.; Patel, U.D.; Ratner, R.E.; Whaley-Connell, A.T.; Molitch, M.E. Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care, 2014, 37(10), 2864-2883.
[http://dx.doi.org/10.2337/dc14-1296] [PMID: 25249672]
[48]
Voziyan, P.; Brown, K.L.; Chetyrkin, S.; Hudson, B. Site-specific AGE modifications in the extracellular matrix: a role for glyoxal in protein damage in diabetes. Clin. Chem. Lab. Med., 2014, 52(1), 39-45.
[http://dx.doi.org/10.1515/cclm-2012-0818] [PMID: 23492568]
[49]
Ceriello, A.; Motz, E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler. Thromb. Vasc. Biol., 2004, 24(5), 816-823.
[http://dx.doi.org/10.1161/01.ATV.0000122852.22604.78] [PMID: 14976002]
[50]
Fiorentino, T.V.; Prioletta, A.; Zuo, P.; Folli, F. Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Curr. Pharm. Des., 2013, 19(32), 5695-5703.
[http://dx.doi.org/10.2174/1381612811319320005] [PMID: 23448484]
[51]
Gould, N.; Doulias, P.T.; Tenopoulou, M.; Raju, K.; Ischiropoulos, H. Regulation of protein function and signaling by reversible cysteine S-nitrosylation. J. Biol. Chem., 2013, 288(37), 26473-26479.
[http://dx.doi.org/10.1074/jbc.R113.460261] [PMID: 23861393]
[52]
Beisswenger, P.J.; Howell, S.K.; Russell, G.B.; Miller, M.E.; Rich, S.S.; Mauer, M. Early progression of diabetic nephropathy correlates with methylglyoxal-derived advanced glycation end products. Diabetes Care, 2013, 36(10), 3234-3239.
[http://dx.doi.org/10.2337/dc12-2689] [PMID: 23780945]
[53]
Saisho, Y.; Maruyama, T.; Hirose, H.; Saruta, T. Relationship between proinsulin-to-insulin ratio and advanced glycation endproducts in Japanese type 2 diabetic subjects. Diabetes Res. Clin. Pract., 2007, 78(2), 182-188.
[http://dx.doi.org/10.1016/j.diabres.2007.03.014] [PMID: 17467843]
[54]
Toth-Manikowski, S.; Atta, M.G. Diabetic kidney disease: pathophysiology and therapeutic targets. J. Diabetes Res., 2015, 2015697010
[http://dx.doi.org/10.1155/2015/697010] [PMID: 26064987]
[55]
Satirapoj, B. Nephropathy in diabetes. Adv. Exp. Med. Biol., 2012, 771, 107-122.
[http://dx.doi.org/10.1007/978-1-4614-5441-0_11] [PMID: 23393675]
[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]
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]
[58]
Iacobini, C.; Menini, S.; Blasetti Fantauzzi, C.; Pesce, C.M.; Giaccari, A.; Salomone, E.; Lapolla, A.; Orioli, M.; Aldini, G.; Pugliese, G. FL-926-16, a novel bioavailable carnosinase-resistant carnosine derivative, prevents onset and stops progression of diabetic nephropathy in db/db mice. Br. J. Pharmacol., 2018, 175(1), 53-66.
[http://dx.doi.org/10.1111/bph.14070] [PMID: 29053168]
[59]
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]
[60]
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]
[61]
Anderson, E.J.; Vistoli, G.; Katunga, L.A.; Funai, K.; Regazzoni, L.; Monroe, T.B.; Gilardoni, E.; Cannizzaro, L.; Colzani, M.; De Maddis, D.; Rossoni, G.; Canevotti, R.; Gagliardi, S.; Carini, M.; Aldini, G. A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress. J. Clin. Invest., 2018, 128(12), 5280-5293.
[http://dx.doi.org/10.1172/JCI94307] [PMID: 30226473]
[62]
Menini, S.; Iacobini, C.; Ricci, C.; Scipioni, A.; Blasetti Fantauzzi, C.; Giaccari, A.; Salomone, E.; Canevotti, R.; Lapolla, A.; Orioli, M.; Aldini, G.; Pugliese, G. D-Carnosine octylester attenuates atherosclerosis and renal disease in ApoE null mice fed a Western diet through reduction of carbonyl stress and inflammation. Br. J. Pharmacol., 2012, 166(4), 1344-1356.
[http://dx.doi.org/10.1111/j.1476-5381.2012.01834.x] [PMID: 22229552]
[63]
Tamura, Y.; Murayama, T.; Minami, M.; Yokode, M.; Arai, H. Differential effect of statins on diabetic nephropathy in db/db mice. Int. J. Mol. Med., 2011, 28(5), 683-687.
[PMID: 21833465]
[64]
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]
[65]
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]
[66]
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]
[67]
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]
[68]
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]
[69]
Cripps, M.J.; Hanna, K.; Lavilla, C., Jr; Sayers, S.R.; Caton, P.W.; Sims, C.; De Girolamo, L.; Sale, C.; Turner, M.D. Carnosine scavenging of glucolipotoxic free radicals enhances insulin secretion and glucose uptake. Sci. Rep., 2017, 7(1), 13313.
[http://dx.doi.org/10.1038/s41598-017-13649-w] [PMID: 29042678]
[70]
Miceli, V.; Pampalone, M.; Frazziano, G.; Grasso, G.; Rizzarelli, E.; Ricordi, C.; Casu, A.; Iannolo, G.; Conaldi, P.G. Carnosine protects pancreatic beta cells and islets against oxidative stress damage. Mol. Cell. Endocrinol., 2018, 474, 105-118.
[http://dx.doi.org/10.1016/j.mce.2018.02.016] [PMID: 29496567]
[71]
Forsberg, E.A.; Botusan, I.R.; Wang, J.; Peters, V.; Ansurudeen, I.; Brismar, K.; Catrina, S.B. Carnosine decreases IGFBP1 production in db/db mice through suppression of HIF-1. J. Endocrinol., 2015, 225(3), 159-167.
[http://dx.doi.org/10.1530/JOE-14-0571] [PMID: 25869614]
[72]
Aydın, A.F.; Bingül, İ.; Küçükgergin, C.; Doğan-Ekici, I.; Doğru Abbasoğlu, S.; Uysal, M. Carnosine decreased oxidation and glycation products in serum and liver of high-fat diet and low-dose streptozotocin-induced diabetic rats. Int. J. Exp. Pathol., 2017, 98(5), 278-288.
[http://dx.doi.org/10.1111/iep.12252] [PMID: 29205589]
[73]
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]
[74]
Kim, M.Y.; Kim, E.J.; Kim, Y.N.; Choi, C.; Lee, B.H. Effects of α-lipoic acid and L-carnosine supplementation on antioxidant activities and lipid profiles in rats. Nutr. Res. Pract., 2011, 5(5), 421-428.
[http://dx.doi.org/10.4162/nrp.2011.5.5.421] [PMID: 22125679]
[75]
Prokopieva, V.D.; Yarygina, E.G.; Bokhan, N.A.; Ivanova, S.A. Use of carnosine for oxidative stress reduction in different pathologies. Oxid. Med. Cell. Longev., 2016, 20162939087
[http://dx.doi.org/10.1155/2016/2939087] [PMID: 26904160]
[76]
Aydın, A.F.; Küçükgergin, C.; Çoban, J.; Doğan-Ekici, I.; Doğru-Abbasoğlu, S.; Uysal, M.; Koçak-Toker, N. Carnosine prevents testicular oxidative stress and advanced glycation end product formation in D-galactose-induced aged rats. Andrologia, 2018, 50(3), 50.
[http://dx.doi.org/10.1111/and.12939] [PMID: 29230838]
[77]
Aydin, F.; Kalaz, E.B.; Kucukgergin, C.; Coban, J. Dogru- Abbasoglu, S.; Uysal, M. Carnosine treatment diminished oxidative stress and glycation products in serum and tissues of d-galactose-treated rats. Curr. Aging Sci., 2018, 11(1), 10-15.
[http://dx.doi.org/10.2174/1871530317666170703123519] [PMID: 28676006]
[78]
Yılmaz, Z.; Kalaz, E.B.; Aydın, A.F.; Soluk-Tekkeşin, M.; Doğru-Abbasoğlu, S.; Uysal, M.; Koçak-Toker, N. The effect of carnosine on methylglyoxal-induced oxidative stress in rats. Arch. Physiol. Biochem., 2017, 123(3), 192-198.
[http://dx.doi.org/10.1080/13813455.2017.1296468] [PMID: 28276708]
[79]
Peters, V.; Calabrese, V.; Forsberg, E.; Volk, N.; Fleming, T.; Baelde, H.; Weigand, T.; Thiel, C.; Trovato, A.; Scuto, M.; Modafferi, S.; Schmitt, C.P. protective actions of anserine under diabetic conditions. Int. J. Mol. Sci., 2018, 19(9), 19.
[http://dx.doi.org/10.3390/ijms19092751] [PMID: 30217069]
[80]
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]
[81]
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]
[82]
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, 20179506730
[http://dx.doi.org/10.1155/2017/9506730] [PMID: 28553654]
[83]
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]
[84]
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]
[85]
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]
[86]
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]
[87]
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]
[88]
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]
[89]
Peters, V.; Kebbewar, M.; Janssen, B.; Hoffmann, G.F.; Moller, 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]
[90]
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]
[91]
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]
[92]
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]
[93]
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]
[94]
Houjeghani, S.; Kheirouri, S.; Faraji, E.; Jafarabadi, M.A. l-Carnosine supplementation attenuated fasting glucose, triglycerides, advanced glycation end products, and tumor necrosis factor-α levels in patients with type 2 diabetes: a double-blind placebo-controlled randomized clinical trial. Nutr. Res., 2018, 49, 96-106.
[http://dx.doi.org/10.1016/j.nutres.2017.11.003] [PMID: 29420997]
[95]
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]
[96]
Spelnikov, D.; Harris, R.C. A kinetic model of carnosine synthesis in human skeletal muscle. Amino Acids, 2019, 51(1), 115-121.
[http://dx.doi.org/10.1007/s00726-018-2646-z] [PMID: 30209603]
[97]
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, 2019, 51(1), 7-16.
[http://dx.doi.org/10.1007/s00726-018-2601-z] [PMID: 29922921]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 27
ISSUE: 11
Year: 2020
Published on: 22 April, 2020
Page: [1801 - 1812]
Pages: 12
DOI: 10.2174/0929867326666190326111851
Price: $65

Article Metrics

PDF: 67
HTML: 9



Related Article(s)

Most Downloaded Article(s)