{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:09:42Z","timestamp":1791288582214,"version":"4.3.0"},"reference-count":33,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,11,25]],"date-time":"2021-11-25T00:00:00Z","timestamp":1637798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>One of the most important risk factors for developing chronic kidney disease (CKD) is diabetes. To assess the safety and efficacy of potential drug candidates, reliable animal models that mimic human diseases are crucial. However, a suitable model of diabetic kidney disease (DKD) is currently not available. The aim of this study is to develop a rat model of DKD by combining streptozotocin and nicotinamide (STZ\/NAD) with oral N(\u03c9)-Nitro-L-Arginine Methyl Ester (L-NAME) administration. Diabetes was induced in male Wistar rats by intravenous injection of 65 mg\/kg STZ, 15 min after intraperitoneal injection of 230 mg\/kg NAD. Rats were assigned to different groups receiving L-NAME (100 mg\/kg\/day) (STZ\/NAD\/L-NAME) or vehicle (STZ\/NAD) for a period of 9 or 12 weeks by daily oral gavage. All rats developed hyperglycemia. Hyperfiltration was observed at the start of the study, whereas increased serum creatinine, albumin-to-creatinine ratio, and evolving hypofiltration were detected at the end of the study. Daily L-NAME administration caused a rapid rise in blood pressure. Histopathological evaluation revealed heterogeneous renal injury patterns, which were most severe in the STZ\/NAD\/L-NAME rats. L-NAME-induced NO-deficiency in STZ\/NAD-induced diabetic rats leads to multiple characteristic features of human DKD and may represent a novel rat model of DKD.<\/jats:p>","DOI":"10.3390\/ijms222312767","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T04:48:37Z","timestamp":1638247717000},"page":"12767","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["L-NAME Administration Enhances Diabetic Kidney Disease Development in an STZ\/NAD Rat Model"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5380-3825","authenticated-orcid":false,"given":"Rapha\u00eblle","family":"Corremans","sequence":"first","affiliation":[{"name":"Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1463-6571","authenticated-orcid":false,"given":"Patrick C.","family":"D\u2019Haese","sequence":"additional","affiliation":[{"name":"Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8589-5469","authenticated-orcid":false,"given":"Benjamin A.","family":"Vervaet","sequence":"additional","affiliation":[{"name":"Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Verhulst","sequence":"additional","affiliation":[{"name":"Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1681\/ASN.2016060666","article-title":"Glomerular Hyperfiltration in Diabetes: Mechanisms, Clinical Significance, and Treatment","volume":"28","author":"Tonneijck","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_2","first-page":"49","article-title":"Diabetic kidney disease: World-wide difference of prevalence and risk factors","volume":"5","author":"Gheith","year":"2015","journal-title":"J. Nephropharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.kisu.2017.10.003","article-title":"Diagnosis of diabetic kidney disease: State of the art and future perspective","volume":"8","author":"Persson","year":"2018","journal-title":"Kidney Int. Suppl."},{"key":"ref_4","unstructured":"Clarkson, M., Brenner, B., and Magee, C. (2010). Diabetic Nephropathy. Pocket Companion to Brenner and Rector\u2019s the Kidney, Saunders\/Elsevier. [8th ed.]."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1242\/dmm.027276","article-title":"Renal disease pathophysiology and treatment: Contributions from the rat","volume":"9","author":"Mullins","year":"2016","journal-title":"Dis. Model. Mech."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s11892-015-0706-2","article-title":"An Update on the Use of Animal Models in Diabetic Nephropathy Research","volume":"16","author":"Betz","year":"2016","journal-title":"Curr. Diabetes Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.phrs.2015.08.023","article-title":"Potential impact of sitagliptin on collagen-derived dipeptides in diabetic osteoporosis","volume":"100","author":"Baerts","year":"2015","journal-title":"Pharmacol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4239\/wjd.v3.i1.1","article-title":"Renal hyperfiltration related to diabetes mellitus and obesity in human disease","volume":"3","author":"Sasson","year":"2012","journal-title":"World J. Diabetes"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nrneph.2012.19","article-title":"Glomerular hyperfiltration: Definitions, mechanisms and clinical implications","volume":"8","author":"Helal","year":"2012","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/j.1524-6175.2006.06032.x","article-title":"Nitric Oxide in Hypertension","volume":"8","author":"Hermann","year":"2006","journal-title":"J. Clin. Hypertens."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.cjca.2018.01.010","article-title":"Pathophysiological Links Between Diabetes and Blood Pressure","volume":"34","author":"Libianto","year":"2018","journal-title":"Can. J. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41401-018-0042-6","article-title":"Vascular endothelial dysfunction, a major mediator in diabetic cardiomyopathy","volume":"40","author":"Knapp","year":"2018","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"F317","DOI":"10.1152\/ajprenal.90450.2008","article-title":"Endothelial injury due to eNOS deficiency accelerates the progression of chronic renal disease in the mouse","volume":"296","author":"Nakayama","year":"2009","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/hr.2010.263","article-title":"The contribution of hypertension to diabetic nephropathy and retinopathy: The role of inflammation and oxidative stress","volume":"34","author":"Silva","year":"2011","journal-title":"Hypertens. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"175","DOI":"10.2337\/diaspect.28.3.175","article-title":"Hypertension Management in Diabetic Kidney Disease","volume":"28","author":"Patney","year":"2015","journal-title":"Diabetes Spectr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"279","DOI":"10.2147\/IJNRD.S103784","article-title":"Rodent models of diabetic nephropathy: Their utility and limitations","volume":"9","author":"Kitada","year":"2016","journal-title":"Int. J. Nephrol. Renov. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1056\/NEJMoa1303154","article-title":"Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy","volume":"369","author":"Fried","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.kint.2016.01.023","article-title":"An autopsy study suggests that diabetic nephropathy is underdiagnosed","volume":"90","author":"Klessens","year":"2016","journal-title":"Kidney Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1748-1716.2010.02147.x","article-title":"Tubular reabsorption and diabetes-induced glomerular hyperfiltration","volume":"200","author":"Persson","year":"2010","journal-title":"Acta Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1536\/ihj.37.153","article-title":"Tubuloglomerular Feedback","volume":"37","author":"Ito","year":"1996","journal-title":"Jpn. Heart J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1007\/s00125-010-1794-9","article-title":"The clinical significance of hyperfiltration in diabetes","volume":"53","author":"Jerums","year":"2010","journal-title":"Diabetologia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1056\/NEJMoa1811744","article-title":"Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy","volume":"380","author":"Perkovic","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/S2213-8587(19)30256-6","article-title":"SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: A systematic review and meta-analysis","volume":"7","author":"Neuen","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1146\/annurev.pathol.4.110807.092150","article-title":"A Glimpse of Various Pathogenetic Mechanisms of Diabetic Nephropathy","volume":"6","author":"Kanwar","year":"2011","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1111\/jvim.15454","article-title":"The renin-angiotensin-aldosterone system and its suppression","volume":"33","author":"Ames","year":"2018","journal-title":"J. Vet. Intern. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/sj.jhh.1001982","article-title":"Evidence for renoprotection by blockade of the renin\u2013angiotensin\u2013aldosterone system in hypertension and diabetes","volume":"20","author":"Karalliedde","year":"2006","journal-title":"J. Hum. Hypertens."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.2215\/CJN.04510512","article-title":"Glomerular and Tubular Damage Markers in Individuals with Progressive Albuminuria","volume":"8","author":"Nauta","year":"2013","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1038\/hr.2012.138","article-title":"Endothelial dysfunction and hypertension in aging","volume":"35","author":"Higashi","year":"2012","journal-title":"Hypertens. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.3389\/fphar.2019.01677","article-title":"Hypertensive Rats Treated Chronically With N\u03c9-Nitro-L-Arginine Methyl Ester (L-NAME) Induced Disorder of Hepatic Fatty Acid Metabolism and Intestinal Pathophysiology","volume":"10","author":"Li","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1291\/hypres.31.793","article-title":"Regression of L-NAME\u2013Induced Hypertension: The Role of Nitric Oxide and Endothelium-Derived Constricting Factor","volume":"31","author":"Paulis","year":"2008","journal-title":"Hypertens. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"101238","DOI":"10.1016\/j.redox.2019.101238","article-title":"L-NAME releases nitric oxide and potentiates subsequent nitroglycerin-mediated vasodilation","volume":"26","author":"Liu","year":"2019","journal-title":"Redox Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s40620-020-00797-y","article-title":"Renal structure in type 2 diabetes: Facts and misconceptions","volume":"33","author":"Bettini","year":"2020","journal-title":"J. Nephrol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1007\/s00125-008-1051-7","article-title":"The kidney in diabetes: Dynamic pathways of injury and repair. The Camillo Golgi Lecture 2007","volume":"51","author":"Fioretto","year":"2008","journal-title":"Diabetologia"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/23\/12767\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:35:59Z","timestamp":1760168159000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/23\/12767"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,25]]},"references-count":33,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["ijms222312767"],"URL":"https:\/\/doi.org\/10.3390\/ijms222312767","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,25]]}}}