{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:44:00Z","timestamp":1790682240013,"version":"4.1.0"},"reference-count":34,"publisher":"Portland Press Ltd.","issue":"23","license":[{"start":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T00:00:00Z","timestamp":1606348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,12,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Diabetic nephropathy (DN) is a common microvascular complication of diabetes and the main cause of end-stage nephropathy (ESRD). Inflammation and fibrosis play key roles in the development and progression of diabetic nephropathy. By using in vivo and in vitro DN models, our laboratory has identified the protective role of carnosine (CAR) on renal tubules. Our results showed that carnosine restored the onset and clinical symptoms as well as renal tubular injury in DN. Furthermore, carnosine decreased kidney inflammation and fibrosis in DN mice. These results were consistent with high glucose (HG)-treated mice tubular epithelial cells (MTECs). Using web-prediction algorithms, cellular thermal shift assay (CETSA) and molecular docking, we identified glycine N-methyltransferase (GNMT) as a carnosine target. Importantly, we found that GNMT, a multiple functional protein that regulates the cellular pool of methyl groups by controlling the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), was down-regulated significantly in the serum of Type 1 DM patients and renal tissues of DN mice. Moreover, using cultured TECs, we confirmed that the increased GNMT expression by transient transfection mimicked the protective role of carnosine in reducing inflammation and fibrosis. Conversely, the inhibition of GNMT expression abolished the protective effects of carnosine. In conclusion, carnosine might serve as a promising therapeutic agent for DN and GNMT might be a potential therapeutic target for DN.<\/jats:p>","DOI":"10.1042\/cs20201207","type":"journal-article","created":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T10:40:52Z","timestamp":1606387252000},"page":"3175-3193","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Carnosine alleviates diabetic nephropathy by targeting GNMT, a key enzyme mediating renal inflammation and fibrosis"],"prefix":"10.1042","volume":"134","author":[{"given":"Xue-qi","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-yong","family":"Nie","sequence":"additional","affiliation":[{"name":"Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Scientific Research of Anhui Medical University, Hefei, Anhui 230022, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-xu","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benito","family":"Yard","sequence":"additional","affiliation":[{"name":"Vth Department of Medicine (Nephrology\/Endocrinology\/Rheumatology) University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer1-3, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6434-4759","authenticated-orcid":false,"given":"Yong-gui","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China"},{"name":"Center for Scientific Research of Anhui Medical University, Hefei, Anhui 230022, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2020,12,9]]},"reference":[{"key":"2021113011175393600_B1","doi-asserted-by":"publisher","first-page":"9279","DOI":"10.1096\/fj.201802427RRR","article-title":"Exosomes from high glucose-treated macrophages activate glomerular mesangial cells via TGF-beta1\/Smad3 pathway in vivo and in vitro","volume":"33","author":"Zhu","year":"2019","journal-title":"FASEB J."},{"key":"2021113011175393600_B2","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.redox.2018.02.013","article-title":"Reactive oxygen species promote tubular injury in diabetic nephropathy: The role of the mitochondrial ros-txnip-nlrp3 biological axis","volume":"16","author":"Han","year":"2018","journal-title":"Redox. Biol."},{"key":"2021113011175393600_B3","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1016\/j.ajpath.2012.08.014","article-title":"Kidney proximal tubular epithelial-specific overexpression of netrin-1 suppresses inflammation and albuminuria through suppression of COX-2-mediated PGE2 production in streptozotocin-induced diabetic mice","volume":"181","author":"Mohamed","year":"2012","journal-title":"Am. J. Pathol."},{"key":"2021113011175393600_B4","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1681\/ASN.2017040371","article-title":"Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy","volume":"29","author":"Hinden","year":"2018","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021113011175393600_B5","doi-asserted-by":"publisher","first-page":"4523","DOI":"10.1038\/s41467-019-12433-w","article-title":"Arctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes","volume":"10","author":"Zhong","year":"2019","journal-title":"Nat. Commun."},{"key":"2021113011175393600_B6","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/S0014-2999(03)02079-X","article-title":"Preventive effect of l-carnosine on ischemia\/reperfusion-induced acute renal failure in rats","volume":"474","author":"Fujii","year":"2003","journal-title":"Eur. J. Pharmacol."},{"key":"2021113011175393600_B7","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1007\/s12291-010-0018-x","article-title":"Antioxidant effect of carnosine pretreatment on cisplatin-induced renal oxidative stress in rats","volume":"25","author":"Noori","year":"2010","journal-title":"Indian J. Clin. Biochem."},{"key":"2021113011175393600_B8","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1124\/jpet.106.110122","article-title":"Renoprotective effects of l-carnosine on ischemia\/reperfusion-induced renal injury in rats","volume":"319","author":"Kurata","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021113011175393600_B9","doi-asserted-by":"publisher","first-page":"6960","DOI":"10.1038\/s41598-018-22298-6","article-title":"Glycine N-methyltransferase inhibits aristolochic acid nephropathy by increasing CYP3A44 and decreasing NQO1 expression in female mouse hepatocytes","volume":"8","author":"Chang","year":"2018","journal-title":"Sci. Rep."},{"key":"2021113011175393600_B10","doi-asserted-by":"publisher","first-page":"281","DOI":"10.3390\/antiox8080281","article-title":"Carnosine Decreases PMA-Induced Oxidative Stress and Inflammation in Murine Macrophages","volume":"8,","author":"Caruso","year":"2019","journal-title":"Antioxidants (Basel)"},{"key":"2021113011175393600_B11","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.2174\/092986732711200423112140","article-title":"Dysregulation of Carnosine Metabolism in Progression of Diseases","volume":"27","author":"Bozko","year":"2020","journal-title":"Curr. Med. Chem."},{"key":"2021113011175393600_B12","doi-asserted-by":"publisher","first-page":"1764","DOI":"10.2174\/0929867326666190730130024","article-title":"Carnosine and Kidney Diseases: What We Currently Know?","volume":"27","author":"Kilis-Pstrusinska","year":"2020","journal-title":"Curr. Med. Chem."},{"key":"2021113011175393600_B13","doi-asserted-by":"publisher","first-page":"1689","DOI":"10.1681\/ASN.2015040415","article-title":"Interaction of the EGF Receptor and the Hippo Pathway in the Diabetic Kidney","volume":"27","author":"Chen","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021113011175393600_B14","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1016\/j.kint.2018.06.006","article-title":"The angiotensin II type 2 receptors protect renal tubule mitochondria in early stages of diabetes mellitus","volume":"94","author":"Micakovic","year":"2018","journal-title":"Kidney Int."},{"key":"2021113011175393600_B15","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.intimp.2018.03.019","article-title":"Inhibitor of Bruton's tyrosine kinases, PCI-32765, decreases pro-inflammatory mediators' production in high glucose-induced macrophages","volume":"58","author":"Fan","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"2021113011175393600_B16","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.cyto.2015.11.023","article-title":"Blockade of TGF-beta-activated kinase 1 prevents advanced glycation end products-induced inflammatory response in macrophages","volume":"78","author":"Xu","year":"2016","journal-title":"Cytokine"},{"key":"2021113011175393600_B17","doi-asserted-by":"publisher","first-page":"2642","DOI":"10.1111\/bph.14687","article-title":"Blockade of myeloid differentiation 2 attenuates diabetic nephropathy by reducing activation of the renin-angiotensin system in mouse kidneys","volume":"176","author":"Wang","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"2021113011175393600_B18","doi-asserted-by":"publisher","first-page":"2749","DOI":"10.1111\/jcmm.14946","article-title":"Cyclin G2 regulates canonical Wnt signalling via interaction with Dapper1 to attenuate tubulointerstitial fibrosis in diabetic nephropathy","volume":"24","author":"Zhao","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"2021113011175393600_B19","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1038\/s41419-019-2085-0","article-title":"Inhibition of STAT3 in tubular epithelial cells prevents kidney fibrosis and nephropathy in STZ-induced diabetic mice","volume":"10","author":"Zheng","year":"2019","journal-title":"Cell Death Dis."},{"key":"2021113011175393600_B20","doi-asserted-by":"publisher","first-page":"e2937","DOI":"10.1038\/cddis.2017.292","article-title":"Interleukin-22 ameliorated renal injury and fibrosis in diabetic nephropathy through inhibition of NLRP3 inflammasome activation","volume":"8","author":"Wang","year":"2017","journal-title":"Cell Death Dis."},{"key":"2021113011175393600_B21","doi-asserted-by":"publisher","first-page":"104600","DOI":"10.1016\/j.phrs.2019.104600","article-title":"Mitochondrial carnitine palmitoyltransferase 2 is involved in N(epsilon)-(carboxymethyl)-lysine-mediated diabetic nephropathy","volume":"152","author":"Lee","year":"2020","journal-title":"Pharmacol. Res."},{"key":"2021113011175393600_B22","doi-asserted-by":"publisher","first-page":"154258","DOI":"10.1016\/j.metabol.2020.154258","article-title":"Targeting mammalian serine\/threonine-protein kinase 4 through yes-associated protein\/TEA domain transcription factor-mediated epithelial-mesenchymal transition ameliorates diabetic nephropathy orchestrated renal fibrosis","volume":"108","author":"Yang","year":"2020","journal-title":"Metabolism"},{"key":"2021113011175393600_B23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.lfs.2019.03.073","article-title":"Luteolin attenuates high glucose-induced podocyte injury via suppressing NLRP3 inflammasome pathway","volume":"225","author":"Yu","year":"2019","journal-title":"Life Sci."},{"key":"2021113011175393600_B24","doi-asserted-by":"publisher","first-page":"114132","DOI":"10.1016\/j.bcp.2020.114132","article-title":"Rutaecarpine derivative Cpd-6c alleviates acute kidney injury by targeting PDE4B, a key enzyme mediating inflammation in cisplatin nephropathy","volume":"180","author":"Liu","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"2021113011175393600_B25","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1159\/000491905","article-title":"Rapamycin Reduces Podocyte Apoptosis and is Involved in Autophagy and mTOR\/ P70S6K\/4EBP1 Signaling","volume":"48","author":"Jin","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"2021113011175393600_B26","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1007\/s00018-017-2639-1","article-title":"Autophagy in diabetic kidney disease: regulation, pathological role and therapeutic potential","volume":"75","author":"Yang","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"2021113011175393600_B27","doi-asserted-by":"publisher","first-page":"13802","DOI":"10.1038\/s41598-018-30800-3","article-title":"AAV serotype 8-mediated liver specific GNMT expression delays progression of hepatocellular carcinoma and prevents carbon tetrachloride-induced liver damage","volume":"8","author":"Fang","year":"2018","journal-title":"Sci. Rep."},{"key":"2021113011175393600_B28","doi-asserted-by":"publisher","first-page":"3230490","DOI":"10.1155\/2020\/3230490","article-title":"Dexmedetomidine Preconditioning Protects Rats from Renal Ischemia-Reperfusion Injury Accompanied with Biphasic Changes of Nuclear Factor-Kappa B Signaling","volume":"2020","author":"Bao","year":"2020","journal-title":"J. Immunol. Res."},{"key":"2021113011175393600_B29","doi-asserted-by":"publisher","first-page":"279","DOI":"10.3177\/jnsv.24.279","article-title":"Effect of dietary methionine level on anserine and carnosine contents in the gastrocnemius muscle of rat","volume":"24","author":"Tamaki","year":"1978","journal-title":"J. Nutr. Sci. Vitaminol. (Tokyo)"},{"key":"2021113011175393600_B30","doi-asserted-by":"publisher","first-page":"1968","DOI":"10.1038\/s41598-018-37292-1","article-title":"Induction of GNMT by 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranoside through proteasome-independent MYC downregulation in hepatocellular carcinoma","volume":"9","author":"Kant","year":"2019","journal-title":"Sci. Rep."},{"key":"2021113011175393600_B31","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.molmet.2019.08.008","article-title":"miR-873-5p targets mitochondrial GNMT-Complex II interface contributing to non-alcoholic fatty liver disease","volume":"29","author":"Fernandez-Tussy","year":"2019","journal-title":"Mol. Metab."},{"key":"2021113011175393600_B32","doi-asserted-by":"publisher","first-page":"663e6","DOI":"10.1016\/j.celrep.2018.09.065","article-title":"Sarcosine Is Uniquely Modulated by Aging and Dietary Restriction in Rodents and Humans","volume":"25","author":"Walters","year":"2018","journal-title":"Cell Rep."},{"key":"2021113011175393600_B33","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.bbapap.2011.10.008","article-title":"Differences in folate-protein interactions result in differing inhibition of native rat liver and recombinant glycine N-methyltransferase by 5-methyltetrahydrofolate","volume":"1824","author":"Luka","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"2021113011175393600_B34","doi-asserted-by":"publisher","first-page":"4489","DOI":"10.18632\/aging.102902","article-title":"Methionine abrogates the renoprotective effect of a low-protein diet against diabetic kidney disease in obese rats with type 2 diabetes","volume":"12","author":"Kitada","year":"2020","journal-title":"Aging (Albany NY)"}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/134\/23\/3175\/899307\/cs-2020-1207.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/134\/23\/3175\/899307\/cs-2020-1207.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T12:15:52Z","timestamp":1638274552000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/134\/23\/3175\/227039\/Carnosine-alleviates-diabetic-nephropathy-by"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12]]},"references-count":34,"journal-issue":{"issue":"23","published-print":{"date-parts":[[2020,12,11]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20201207","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,12]]},"published":{"date-parts":[[2020,12]]}}}