{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:40:32Z","timestamp":1790404832840,"version":"4.1.0"},"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T00:00:00Z","timestamp":1701820800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000191","name":"Kidney Foundation of Canada","doi-asserted-by":"publisher","award":["152092"],"award-info":[{"award-number":["152092"]}],"id":[{"id":"10.13039\/501100000191","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Canagliflozin (CANA) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor with blood glucose lowering effects. CANA also promotes kidney protection in patients with cardiovascular diseases and type 2 diabetes (T2D), as well as in normoglycemic patients with hypertension or heart failure. Clinical studies, although conduct in both sexes, do not report sex-dependent differences in T2DM treated with CANA. However, the impact of CANA in type 1 diabetes, as well in sex-dependent outcomes in such cohort needs further understanding. To analyze the effects of CANA in mice with combined hypertension and type 1 diabetes, diabetes was induced by STZ injection (5 days, 50mg\/kg\/day) in both male and female 8 weeks old genetic hypertensive mice (Lin), whereas the control (Lin) received 0.1M sodium citrate injections. 8 weeks after STZ. Mice were fed either regular or CANA-infused diet for 4 weeks. 8 weeks after STZ, hyperglycemia was present in both male and female mice. CANA reversed BG increase mice fed regular diet. Male LinSTZ mice had elevated water intake, urine output, urinary albumin to creatinine ratio (ACR), kidney lesion score, and creatinine clearance compared to the Lin control group. Kidney injury was improved in male LinSTZ + CANA group in male mice. Water intake and urine output were not statistically significantly different in female LinSTZ compared to female LinSTZ+ CANA. Moreover, CANA did not improve kidney injury in female mice, showing no effect in creatinine clearance, lesion score and fibrosis when compared to LinSTZ fed regular diet. Here we show that Canagliflozin might exert different kidney protection effects in male compared to female mice with hypertension and type 1 diabetes. Sex-dimorphisms were previously found in the pathophysiology of diabetes induced by STZ. Therefore, we highlight the importance of in-depth investigation on sex-dependent effects of CANA, taking in consideration the unique characteristics of disease progression for each sex.<\/jats:p>","DOI":"10.1371\/journal.pone.0295284","type":"journal-article","created":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T18:33:13Z","timestamp":1701887593000},"page":"e0295284","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Sex-dependent effects of Canagliflozin on kidney protection in mice with combined hypertension-type 1 diabetes"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2446-7783","authenticated-orcid":true,"given":"Mayra","family":"Trentin-Sonoda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Cheff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Gutsol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1419-7719","authenticated-orcid":true,"given":"Richard L.","family":"H\u00e9bert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,12,6]]},"reference":[{"key":"pone.0295284.ref001","first-page":"V","article-title":"Is Diabetes Becoming the Biggest Epidemic of the Twenty-first Century?","volume":"1","author":"SA Tabish","year":"2007","journal-title":"Int J Health Sci (Qassim)"},{"key":"pone.0295284.ref002","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1161\/01.HYP.0000069699.92349.8C","article-title":"Blood Pressure Predicts Risk of Developing End-Stage Renal Disease in Men and Women","volume":"41","author":"M Tozawa","year":"2003","journal-title":"Hypertension"},{"key":"pone.0295284.ref003","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1093\/ajh\/hpv003","article-title":"Blood Pressure, Proteinuria, and Renal Function Decline: Associations in a Large Community-Based Population","volume":"28","author":"A Hirayama","year":"2015","journal-title":"Am J Hypertens"},{"key":"pone.0295284.ref004","doi-asserted-by":"crossref","first-page":"683","DOI":"10.2337\/diacare.24.4.683","article-title":"Cardiovascular Morbidity and Mortality Associated With the Metabolic Syndrome","volume":"24","author":"B Isomaa","year":"2001","journal-title":"Diabetes Care"},{"key":"pone.0295284.ref005","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1681\/ASN.2010030246","article-title":"SGLT2 Mediates Glucose Reabsorption in the Early Proximal Tubule","volume":"22","author":"V Vallon","year":"2011","journal-title":"JASN"},{"key":"pone.0295284.ref006","doi-asserted-by":"crossref","first-page":"F156","DOI":"10.1152\/ajprenal.00409.2012","article-title":"Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus","volume":"304","author":"V Vallon","year":"2013","journal-title":"Am J Physiol Renal Physiol"},{"key":"pone.0295284.ref007","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/jdi.12214","article-title":"Renal sodium glucose cotransporter 2 inhibitors as a novel therapeutic approach to treatment of type 2 diabetes: Clinical data and mechanism of action","volume":"5","author":"Y Fujita","year":"2014","journal-title":"J Diabetes Invest"},{"key":"pone.0295284.ref008","doi-asserted-by":"crossref","first-page":"745","DOI":"10.14740\/jocmr3112w","article-title":"Effect of Sodium Glucose Cotransporter 2 Inhibitors With Low SGLT2\/SGLT1 Selectivity on Circulating Glucagon-Like Peptide 1 Levels in Type 2 Diabetes Mellitus","volume":"9","author":"K Takebayashi","year":"2017","journal-title":"J Clin Med Res"},{"key":"pone.0295284.ref009","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1097\/MNH.0000000000000724","article-title":"Sodium-glucose cotransporter 2 inhibition in non-diabetic kidney disease","volume":"30","author":"M Almaimani","year":"2021","journal-title":"Current Opinion in Nephrology & Hypertension"},{"key":"pone.0295284.ref010","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1056\/NEJMoa2024816","article-title":"Dapagliflozin in Patients with Chronic Kidney Disease","volume":"383","author":"HJL Heerspink","year":"2020","journal-title":"N Engl J Med"},{"key":"pone.0295284.ref011","doi-asserted-by":"crossref","first-page":"4","DOI":"10.2337\/diaclin.32.1.4","article-title":"SGLT-2 Inhibitors: A New Mechanism for Glycemic Control","volume":"32","author":"EC Chao","year":"2014","journal-title":"Clinical Diabetes"},{"key":"pone.0295284.ref012","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1042\/CS20210094","article-title":"Angiotensin II up-regulates sodium-glucose co-transporter 2 expression and SGLT2 inhibitor attenuates Ang II-induced hypertensive renal injury in mice","volume":"135","author":"KN Miyata","year":"2021","journal-title":"Clin Sci"},{"key":"pone.0295284.ref013","doi-asserted-by":"crossref","first-page":"e025045","DOI":"10.1161\/JAHA.121.025045","article-title":"Effect of Canagliflozin on Total Cardiovascular Burden in Patients With Diabetes and Chronic Kidney Disease: A Post Hoc Analysis From the CREDENCE Trial","volume":"11","author":"J Li","year":"2022","journal-title":"JAHA"},{"key":"pone.0295284.ref014","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":"V Perkovic","year":"2019","journal-title":"N Engl J Med"},{"key":"pone.0295284.ref015","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1053\/j.ajkd.2022.12.015","article-title":"Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial","volume":"82","author":"TW Yi","year":"2023","journal-title":"Am J Kidney Dis"},{"key":"pone.0295284.ref016","doi-asserted-by":"crossref","first-page":"108503","DOI":"10.1016\/j.pharmthera.2023.108503","article-title":"A systematic review on renal effects of SGLT2 inhibitors in rodent models of diabetic nephropathy","volume":"249","author":"A Ashfaq","year":"2023","journal-title":"Pharmacology & Therapeutics"},{"key":"pone.0295284.ref017","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1152\/physiolgenomics.2000.4.1.67","article-title":"Contribution of circulating renin to local synthesis of angiotensin peptides in the heart","volume":"4","author":"G Prescott","year":"2000","journal-title":"Physiol Genomics"},{"key":"pone.0295284.ref018","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1042\/CS20130808","article-title":"Effects of a domain-selective ACE inhibitor in a mouse model of chronic angiotensin II-dependent hypertension","volume":"127","author":"D Burger","year":"2014","journal-title":"Clin Sci"},{"key":"pone.0295284.ref019","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1073\/pnas.79.2.630","article-title":"Multiple low-dose streptozotocin-induced hyperglycemia and insulitis in C57BL mice: Influence of inbred background, sex, and thymus","volume":"79","author":"EH Leiter","year":"1982","journal-title":"Proc Natl Acad Sci USA"},{"key":"pone.0295284.ref020","first-page":"356","article-title":"The streptozotocin-induced diabetic nude mouse model: differences between animals from different sources","volume":"61","author":"ML Graham","year":"2011","journal-title":"Comp Med"},{"key":"pone.0295284.ref021","doi-asserted-by":"crossref","first-page":"e0238727","DOI":"10.1371\/journal.pone.0238727","article-title":"Successful induction of diabetes in mice demonstrates no gender difference in development of early diabetic retinopathy","volume":"15","author":"A Saadane","year":"2020","journal-title":"PLoS ONE"},{"key":"pone.0295284.ref022","doi-asserted-by":"crossref","first-page":"e113459","DOI":"10.1371\/journal.pone.0113459","article-title":"A Novel Mouse Model of Advanced Diabetic Kidney Disease","volume":"9","author":"J-F Thibodeau","year":"2014","journal-title":"PLoS ONE"},{"key":"pone.0295284.ref023","first-page":"50330","article-title":"A High-throughput Method for Measurement of Glomerular Filtration Rate in Conscious Mice","author":"T. Rieg","year":"2013","journal-title":"JoVE"},{"key":"pone.0295284.ref024","doi-asserted-by":"crossref","first-page":"e0281123","DOI":"10.1371\/journal.pone.0281123","article-title":"High fat diet is protective against kidney injury in hypertensive-diabetic mice, but leads to liver injury","volume":"18","author":"V Cheff","year":"2023","journal-title":"PLoS ONE"},{"key":"pone.0295284.ref025","first-page":"dgad249","article-title":"Canagliflozin and Metabolic Associated Fatty Liver Disease in Patients With Diabetes Mellitus: New Insights From CANVAS","author":"AN Borisov","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"key":"pone.0295284.ref026","article-title":"Streptozotocin\u2010Induced Diabetic Models in Mice and Rats","volume":"40","author":"KK Wu","year":"2008","journal-title":"Curr Protoc Pharmacol"},{"key":"pone.0295284.ref027","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1681\/ASN.2012070739","article-title":"Renal Lesions Predict Progression of Diabetic Nephropathy in Type 1 Diabetes","volume":"24","author":"ML Caramori","year":"2013","journal-title":"J Am Soc Nephrol"},{"key":"pone.0295284.ref028","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.2337\/dc12-2391","article-title":"Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion","volume":"36","author":"D Polidori","year":"2013","journal-title":"Diabetes Care"},{"key":"pone.0295284.ref029","doi-asserted-by":"crossref","first-page":"209","DOI":"10.2147\/DMSO.S184437","article-title":"Canagliflozin review; safety and efficacy profile in patients with T2DM","volume":"12","author":"H Jakher","year":"2019","journal-title":"DMSO"},{"key":"pone.0295284.ref030","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.5551\/jat.52100","article-title":"Canagliflozin Prevents Diabetes-Induced Vascular Dysfunction in ApoE-Deficient Mice","volume":"27","author":"A Rahadian","year":"2020","journal-title":"JAT"},{"key":"pone.0295284.ref031","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1007\/s11357-022-00610-7","article-title":"Renoprotective effects of empagliflozin in type 1 and type 2 models of diabetic nephropathy superimposed with hypertension","volume":"44","author":"JM Williams","year":"2022","journal-title":"GeroScience"},{"key":"pone.0295284.ref032","doi-asserted-by":"crossref","first-page":"023","DOI":"10.29328\/journal.jcn.1001069","article-title":"Collecting duct PGE2 responses reduce water loss with empagliflozin in mice with type 2 diabetes mellitus","volume":"5","author":"R Nasrallah","year":"2021","journal-title":"J Clini Nephrol"},{"key":"pone.0295284.ref033","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/phar.1881","article-title":"SGLT2 Inhibitors: A Systematic Review of Diabetic Ketoacidosis and Related Risk Factors in the Primary Literature","volume":"37","author":"KR Burke","year":"2017","journal-title":"Pharmacotherapy"},{"key":"pone.0295284.ref034","doi-asserted-by":"crossref","first-page":"m4147","DOI":"10.1136\/bmj.m4147","article-title":"Diabetic ketoacidosis with SGLT2 inhibitors","author":"G Musso","year":"2020","journal-title":"BMJ"},{"key":"pone.0295284.ref035","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.xkme.2019.12.006","article-title":"SGLT2 Inhibitor\u2013Induced Euglycemic Diabetic Ketoacidosis: A Case Report","volume":"2","author":"KM Wang","year":"2020","journal-title":"Kidney Medicine"},{"key":"pone.0295284.ref036","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.pcl.2018.09.006","article-title":"Nephrogenic Diabetes Insipidus","volume":"66","author":"C Kavanagh","year":"2019","journal-title":"Pediatr Clin N Am"},{"key":"pone.0295284.ref037","doi-asserted-by":"crossref","first-page":"845","DOI":"10.2337\/dc22-2003","article-title":"Glomerular Hyperfiltration Predicts Kidney Function Decline and Mortality in Type 1 and Type 2 Diabetes: A 21-Year Longitudinal Study","volume":"46","author":"D Moriconi","year":"2023","journal-title":"Diabetes Care"},{"key":"pone.0295284.ref038","doi-asserted-by":"crossref","first-page":"e000154","DOI":"10.1136\/bmjdrc-2015-000154","article-title":"Understanding CKD among patients with T2DM: prevalence, temporal trends, and treatment patterns\u2014NHANES 2007\u20132012","volume":"4","author":"B Wu","year":"2016","journal-title":"BMJ Open Diab Res Care"},{"key":"pone.0295284.ref039","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1186\/s13104-018-3670-5","article-title":"Diabetic nephropathy and hypertension in diabetes patients of sub-Saharan countries: a systematic review and meta-analysis","volume":"11","author":"F Wagnew","year":"2018","journal-title":"BMC Res Notes"},{"key":"pone.0295284.ref040","doi-asserted-by":"crossref","first-page":"26428","DOI":"10.1038\/srep26428","article-title":"Once daily administration of the SGLT2 inhibitor, empagliflozin, attenuates markers of renal fibrosis without improving albuminuria in diabetic db\/db mice","volume":"6","author":"LA Gallo","year":"2016","journal-title":"Sci Rep"},{"key":"pone.0295284.ref041","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1159\/000499597","article-title":"Canagliflozin Prevents Intrarenal Angiotensinogen Augmentation and Mitigates Kidney Injury and Hypertension in Mouse Model of Type 2 Diabetes Mellitus","volume":"49","author":"TC Woods","year":"2019","journal-title":"Am J Nephrol"},{"key":"pone.0295284.ref042","doi-asserted-by":"crossref","first-page":"522","DOI":"10.3390\/biomedicines10030522","article-title":"The Effect of SGLT2 Inhibition on Diabetic Kidney Disease in a Model of Diabetic Retinopathy","volume":"10","author":"JR Matthews","year":"2022","journal-title":"Biomedicines"},{"key":"pone.0295284.ref043","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1159\/000499486","article-title":"Consequences of Glomerular Hyperfiltration: The Role of Physical Forces in the Pathogenesis of Chronic Kidney Disease in Diabetes and Obesity","volume":"143","author":"A Chagnac","year":"2019","journal-title":"Nephron"},{"key":"pone.0295284.ref044","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1111\/dom.12090","article-title":"Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease","volume":"15","author":"F Yale J \u2010","year":"2013","journal-title":"Diabetes Obes Metab"},{"key":"pone.0295284.ref045","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.jpeds.2012.06.006","article-title":"Glucose Control Predicts 2-Year Change in Lipid Profile in Youth with Type 1 Diabetes","volume":"162","author":"DM Maahs","year":"2013","journal-title":"J Pediatr"},{"key":"pone.0295284.ref046","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1007\/s13105-014-0362-z","article-title":"Histopathological findings of the pancreas, liver, and carbohydrate metabolizing enzymes in STZ-induced diabetic rats improved by administration of myrtenal","volume":"70","author":"A Rathinam","year":"2014","journal-title":"J Physiol Biochem"},{"key":"pone.0295284.ref047","doi-asserted-by":"crossref","first-page":"e132","DOI":"10.18295\/squmj.2016.16.02.002","article-title":"Mechanisms of Diabetes-Induced Liver Damage: The role of oxidative stress and inflammation","volume":"16","author":"J Mohamed","year":"2016","journal-title":"SQUMJ"},{"key":"pone.0295284.ref048","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1002\/osp4.294","article-title":"Efficacy of canagliflozin against nonalcoholic fatty liver disease: a prospective cohort study: Canagliflozin for patients with NAFLD","volume":"4","author":"T Itani","year":"2018","journal-title":"Obes Sci Pract"},{"key":"pone.0295284.ref049","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3390\/metabo11020087","article-title":"The Effects of SGLT2 Inhibitors on Lipid Metabolism","volume":"11","author":"Z Szekeres","year":"2021","journal-title":"Metabolites"},{"key":"pone.0295284.ref050","doi-asserted-by":"crossref","first-page":"140216","DOI":"10.1098\/rsos.140216","article-title":"An investigation of the false discovery rate and the misinterpretation of p -values","volume":"1","author":"D. Colquhoun","year":"2014","journal-title":"R Soc open sci"},{"key":"pone.0295284.ref051","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1207\/s15327957pspr0203_4","article-title":"HARKing: Hypothesizing After the Results are Known","volume":"2","author":"NL Kerr","year":"1998","journal-title":"Pers Soc Psychol Rev"},{"key":"pone.0295284.ref052","doi-asserted-by":"crossref","first-page":"5210","DOI":"10.3390\/ijms24065210","article-title":"Outbred Mice with Streptozotocin-Induced Diabetes Show Sex Differences in Glucose Metabolism","volume":"24","author":"B Kim","year":"2023","journal-title":"IJMS"},{"key":"pone.0295284.ref053","doi-asserted-by":"crossref","first-page":"2346","DOI":"10.1038\/s41598-018-20703-8","article-title":"Diastolic dysfunction is more apparent in STZ-induced diabetic female mice, despite less pronounced hyperglycemia","volume":"8","author":"C Chandramouli","year":"2018","journal-title":"Sci Rep"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0295284","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T18:33:44Z","timestamp":1701887624000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0295284"}},"subtitle":[],"editor":[{"given":"Michael","family":"Bader","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,12,6]]},"references-count":53,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12,6]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0295284","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,6]]}}}