{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T13:14:04Z","timestamp":1774444444562,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Diabetic kidney disease (DKD) affects a substantial proportion of individuals with diabetes mellitus and represents the leading cause of end-stage renal disease worldwide. Familial aggregation studies consistently demonstrate that genetic factors contribute significantly to DKD susceptibility beyond metabolic and hemodynamic determinants. The carnosine dipeptidase 1 (CNDP1) gene on chromosome 18q22.3 has emerged as a compelling susceptibility locus, with a trinucleotide (CTG) repeat polymorphism in exon 2 that encodes the Mannheim variant, which has demonstrated protective associations in selected populations. Individuals homozygous for the shorter (CTG)5 allele exhibit reduced serum carnosinase-1 concentrations and activity, resulting in elevated tissue carnosine levels. Carnosine exerts multiple renoprotective effects, including antioxidant activity, inhibition of advanced glycation end-product formation, and attenuation of profibrotic signaling. Experimental models demonstrate that genetic or pharmacological reduction in carnosinase activity attenuates diabetic kidney injury. Early clinical studies of carnosine supplementation report improvements in albuminuria and oxidative stress markers, though available trials are limited in size, duration, and population scope. Therapeutic targeting of CNDP1 via carnosinase inhibition, therefore, represents a biologically grounded yet still emerging pharmacological strategy. This review synthesizes genetic, molecular, and translational evidence supporting CNDP1 as a model for genetics-informed therapeutic development in DKD, while highlighting important population-specific variation in allele frequencies that constrain universal clinical applicability.<\/jats:p>","DOI":"10.3390\/genes17040367","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T10:07:13Z","timestamp":1774433233000},"page":"367","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CNDP1 and Diabetic Kidney Disease: From Genetic Susceptibility to Therapeutic Targeting"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6410-8536","authenticated-orcid":false,"given":"Bulent Tolga","family":"Delibasi","sequence":"first","affiliation":[{"name":"Long School of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael Ismail","family":"Sarisen","sequence":"additional","affiliation":[{"name":"Department of Biology, Health, and the Environment, University of Texas, San Antonio, TX 78249, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew Thomas","family":"Belitsos","sequence":"additional","affiliation":[{"name":"Department of Biology, Health, and the Environment, University of Texas, San Antonio, TX 78249, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5760-4276","authenticated-orcid":false,"given":"Halil Kutlu","family":"Erol","sequence":"additional","affiliation":[{"name":"Department of Medicine\/Nephrology, University of Arizona College of Medicine, Tucson, AZ 85724, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5780-8209","authenticated-orcid":false,"given":"Tuncay","family":"Delibasi","sequence":"additional","affiliation":[{"name":"Department of Medicine\/Endocrinology, SUNY Upstate Medical University, Syracuse, NY 13210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.2215\/CJN.11491116","article-title":"Diabetic Kidney Disease: Challenges, Progress, and Possibilities","volume":"12","author":"Alicic","year":"2017","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.kint.2022.05.012","article-title":"Molecular Mechanisms and Therapeutic Targets for Diabetic Kidney Disease","volume":"102","author":"Tuttle","year":"2022","journal-title":"Kidney Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.2337\/db21-0839","article-title":"Systematic Heritability and Heritability Enrichment Analysis for Diabetes Complications in UK Biobank and ACCORD Studies","volume":"71","author":"Kim","year":"2022","journal-title":"Diabetes"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.2337\/diabetes.54.8.2320","article-title":"Carnosine as a Protective Factor in Diabetic Nephropathy: Association with a Leucine Repeat of the Carnosinase Gene CNDP1","volume":"54","author":"Janssen","year":"2005","journal-title":"Diabetes"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1093\/ndt\/gfl717","article-title":"A Leucine Repeat in the Carnosinase Gene CNDP1 Is Associated with Diabetic End-Stage Renal Disease in European Americans","volume":"22","author":"Freedman","year":"2007","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1093\/ckj\/sfaa077","article-title":"The Genetic Map of Diabetic Nephropathy: Evidence from a Systematic Review and Meta-Analysis of Genetic Association Studies","volume":"13","author":"Tziastoudi","year":"2020","journal-title":"Clin. Kidney J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1056\/NEJM198905043201801","article-title":"Familial Clustering of Diabetic Kidney Disease. Evidence for Genetic Susceptibility to Diabetic Nephropathy","volume":"320","author":"Seaquist","year":"1989","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.2337\/diabetes.53.9.2449","article-title":"Population-Based Assessment of Familial Clustering of Diabetic Nephropathy in Type 1 Diabetes","volume":"53","author":"Harjutsalo","year":"2004","journal-title":"Diabetes"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0168-8227(99)00007-8","article-title":"Familial Aggregation of Diabetic Kidney Disease in Type 2 Diabetes in South India","volume":"43","author":"Vijay","year":"1999","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.ymgme.2011.02.010","article-title":"Association of Variants in the Carnosine Peptidase 1 Gene (CNDP1) with Diabetic Nephropathy in American Indians","volume":"103","author":"Chakkera","year":"2011","journal-title":"Mol. Genet. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6521","DOI":"10.1074\/jbc.M209764200","article-title":"Sequence Identification and Characterization of Human Carnosinase and a Closely Related Non-Specific Dipeptidase","volume":"278","author":"Teufel","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1007\/s00125-011-2178-5","article-title":"Common Variants in CNDP1 and CNDP2, and Risk of Nephropathy in Type 2 Diabetes","volume":"54","author":"Ahluwalia","year":"2011","journal-title":"Diabetologia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.2337\/db09-1377","article-title":"Association Between CNDP1 Genotype and Diabetic Nephropathy Is Sex Specific","volume":"59","author":"Mooyaart","year":"2010","journal-title":"Diabetes"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"32","DOI":"10.4103\/0971-5916.193280","article-title":"Association of CTG Repeat Polymorphism in Carnosine Dipeptidase 1 (CNDP1) Gene with Diabetic Nephropathy in North Indians","volume":"144","author":"Yadav","year":"2016","journal-title":"Indian J. Med. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kurashige, M., Imamura, M., Araki, S., Suzuki, D., Babazono, T., Uzu, T., Umezono, T., Toyoda, M., Kawai, K., and Imanishi, M. (2013). The Influence of a Single Nucleotide Polymorphism within CNDP1 on Susceptibility to Diabetic Nephropathy in Japanese Women with Type 2 Diabetes. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054064"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"100443","DOI":"10.1016\/j.genrep.2019.100443","article-title":"Investigating the Association of Rs2346061 (CNDP1), Rs7577 (CNDP2), and Rs1801133 (MTHFR) Variants and Homocysteine Level with Diabetic Nephropathy in an Iranian Population","volume":"16","author":"Asgarbeik","year":"2019","journal-title":"Gene Rep."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Huang, Q., An, C., and Tang, S. (2024). Mendelian Randomization Analysis Reveals Causal Factors behind Diabetic Nephropathy. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1444808"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"The GTEx Consortium, Aguet, F., Anand, S., Ardlie, K.G., Gabriel, S., Getz, G.A., Graubert, A., Hadley, K., Handsaker, R.E., and Huang, K.H. (2020). The GTEx Consortium Atlas of Genetic Regulatory Effects across Human Tissues. Science, 369, 1318\u20131330.","DOI":"10.1126\/science.aaz1776"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1007\/s00726-015-2045-7","article-title":"Intrinsic Carnosine Metabolism in the Human Kidney","volume":"47","author":"Peters","year":"2015","journal-title":"Amino Acids"},{"key":"ref_20","unstructured":"Humphreys, B.D. (2026, January 15). Kidney Interactive Transcriptomics (KIT). Humphreys Laboratory, Division of Nephrology, Washington University School of Medicine: St. Louis, MO, USA. Available online: https:\/\/humphreyslab.com\/SingleCell\/."},{"key":"ref_21","first-page":"2159","article-title":"An eQTL Landscape of Kidney Tissue in Human Nephrotic Syndrome","volume":"29","author":"Gillies","year":"2018","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.3390\/molecules19022299","article-title":"Carnosinases, Their Substrates and Diseases","volume":"19","author":"Bellia","year":"2014","journal-title":"Molecules"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3852","DOI":"10.1093\/ndt\/gfr324","article-title":"L-Carnosine Inhibits High-Glucose-Mediated Matrix Accumulation in Human Mesangial Cells by Interfering with TGF- Production and Signalling","volume":"26","author":"Koppel","year":"2011","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Weigand, T., Colbatzky, F., Pfeffer, T., Garbade, S.F., Klingbeil, K., Colbatzky, F., Becker, M., Zemva, J., Bulkescher, R., and Sch\u00fcrfeld, R. (2020). A Global Cndp1-Knock-Out Selectively Increases Renal Carnosine and Anserine Concentrations in an Age- and Gender-Specific Manner in Mice. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21144887"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Pfeffer, T., Wetzel, C., Kirschner, P., Bartosova, M., Poth, T., Schwab, C., Poschet, G., Zemva, J., Bulkescher, R., and Damgov, I. (2023). Carnosinase-1 Knock-Out Reduces Kidney Fibrosis in Type-1 Diabetic Mice on High Fat Diet. Antioxidants, 12.","DOI":"10.3390\/antiox12061270"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1007\/s00109-020-01957-0","article-title":"Human Carnosinase 1 Overexpression Aggravates Diabetes and Renal Impairment in BTBROb\/Ob Mice","volume":"98","author":"Qiu","year":"2020","journal-title":"J. Mol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"F1030","DOI":"10.1152\/ajprenal.00329.2019","article-title":"Carnosinase-1 Overexpression, but Not Aerobic Exercise Training, Affects the Development of Diabetic Nephropathy in BTBR Ob\/Ob Mice","volume":"318","author":"Everaert","year":"2020","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"44492","DOI":"10.1038\/srep44492","article-title":"Carnosine Attenuates the Development of Both Type 2 Diabetes and Diabetic Nephropathy in BTBR Ob\/Ob Mice","volume":"7","author":"Albrecht","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Qiu, J., Yard, B.A., and Kr\u00e4mer, B.K. (2022). Association Between Serum Carnosinase Concentration and Activity and Renal Function Impairment in a Type-2 Diabetes Cohort. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.899057"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s00726-021-02975-z","article-title":"Correlation between Serum Carnosinase Concentration and Renal Damage in Diabetic Nephropathy Patients","volume":"53","author":"Zhou","year":"2021","journal-title":"Amino Acids"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s00726-022-03206-9","article-title":"Serum and Urinary Carnosinase-1 Correlate with Kidney Function and Inflammation","volume":"55","author":"Zhang","year":"2023","journal-title":"Amino Acids"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1111\/pedi.12564","article-title":"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","volume":"19","author":"Elbarbary","year":"2018","journal-title":"Pediatr. Diabetes"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Li, N., Yan, X., and Lin, J. (2025). Effect of Carnosine or Beta-Alanine Supplementation Therapy for Prediabetes or Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. BMC Endocr. Disord., 25.","DOI":"10.1186\/s12902-025-02016-w"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.numecd.2023.10.012","article-title":"Carnosine Supplementation Improves Glucose Control in Adults with Pre-Diabetes and Type 2 Diabetes: A Randomised Controlled Trial","volume":"34","author":"Hariharan","year":"2024","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"561","DOI":"10.2337\/cd24-0012","article-title":"Effect of Carnosine Supplementation as Add-On Therapy with Vitamin B Complex in People with Type 2 Diabetes and Diabetic Neuropathy: A Randomized Controlled Study","volume":"42","author":"Hamouda","year":"2024","journal-title":"Clin. Diabetes"},{"key":"ref_36","first-page":"303","article-title":"Role of Carnosine in Combination with Vitamin B Complex in Preventing the Progression of Diabetic Neuropathy in People with Type 2 Diabetes","volume":"43","author":"Hamouda","year":"2025","journal-title":"Clin. Diabetes"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s00726-018-2601-z","article-title":"Identification and Characterisation of Carnostatine (SAN9812), a Potent and Selective Carnosinase (CN1) Inhibitor with in Vivo Activity","volume":"51","author":"Qiu","year":"2019","journal-title":"Amino Acids"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Regazzoni, L. (2024). State of the Art in the Development of Human Serum Carnosinase Inhibitors. Molecules, 29.","DOI":"10.3390\/molecules29112488"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"42966","DOI":"10.1021\/acsomega.3c06139","article-title":"Binding Modes of Carnostatine, Homocarnosine, and Ophidine to Human Carnosinase 1","volume":"8","author":"Toviwek","year":"2023","journal-title":"ACS Omega"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"123448","DOI":"10.1016\/j.lfs.2025.123448","article-title":"Carnosinase Inhibition Enhances Reactive Species Scavenging in High Fat Diet","volume":"364","author":"Lavilla","year":"2025","journal-title":"Life Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"ii3","DOI":"10.1093\/ndt\/gfab045","article-title":"Precision Medicine Approaches for Diabetic Kidney Disease: Opportunities and Challenges","volume":"36","author":"Tye","year":"2021","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"20543581231209012","DOI":"10.1177\/20543581231209012","article-title":"Precision Medicine in Diabetic Kidney Disease: A Narrative Review Framed by Lived Experience","volume":"10","author":"Downie","year":"2023","journal-title":"Can. J. Kidney Health Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"101804","DOI":"10.1016\/j.gendis.2025.101804","article-title":"Carnosine Dipeptidase(Cndp): An Emerging Therapeutic Target for Metabolic Diseases and Cancers","volume":"13","author":"Zhou","year":"2026","journal-title":"Genes Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"20240982","DOI":"10.1515\/med-2024-0982","article-title":"Comprehensive Pan-Cancer Investigation of Carnosine Dipeptidase 1 and Its Prospective Prognostic Significance in Hepatocellular Carcinoma","volume":"19","author":"Huang","year":"2024","journal-title":"Open Med."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Gomez-Munoz, M.A., Karz, A., and Navarro, M. (2025). The Carnosinase Dipeptidase CNDP1 Is a Novel Metabolic Vulnerability in Brain Metastasis. bioRxiv.","DOI":"10.1101\/2025.03.18.644053"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Liang, I.C., Gilardoni, E., and Berdaweel, I.A. (2025). Low Plasma Carnosinase-1 Activity in Patients with Left Ventricular Systolic Dysfunction. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26062608"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1681\/ASN.0000000718","article-title":"Genome-Wide Association Study of Quantitative Kidney Function in 52,531 Individuals with Diabetes Identifies Five Diabetes-Specific Loci","volume":"36","author":"Cole","year":"2025","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"102249","DOI":"10.1016\/j.xcrm.2025.102249","article-title":"Multimodal Analysis Stratifies Genetic Susceptibility and Reveals the Pathogenic Mechanism of Kidney Injury in Diabetic Nephropathy","volume":"6","author":"Jiang","year":"2025","journal-title":"Cell Rep. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"148724","DOI":"10.1016\/j.gene.2024.148724","article-title":"T2DM\/CKD Genetic Risk Scores and the Progression of Diabetic Kidney Disease in T2DM Subjects","volume":"927","year":"2024","journal-title":"Gene"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"103860","DOI":"10.1016\/j.drudis.2023.103860","article-title":"Human Carnosinases: A Brief History, Medicinal Relevance, and in Silico Analyses","volume":"29","author":"Chmielewska","year":"2024","journal-title":"Drug Discov. Today"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"D1016","DOI":"10.1093\/nar\/gkae1080","article-title":"Harmonizome 3.0: Integrated Knowledge about Genes and Proteins from Diverse Multi-Omics Resources","volume":"53","author":"Diamant","year":"2025","journal-title":"Nucleic Acids Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/4\/367\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T10:27:57Z","timestamp":1774434477000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/4\/367"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,24]]},"references-count":51,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["genes17040367"],"URL":"https:\/\/doi.org\/10.3390\/genes17040367","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,24]]}}}