{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:46:31Z","timestamp":1790822791725,"version":"4.1.0"},"reference-count":32,"publisher":"Institute of Physiology of the Czech Academy of Sciences","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Physiol Res"],"abstract":"<jats:p>Diabetic nephropathy, included in diabetic kidney disease (DKD), is the primary disease leading to end-stage renal disease (ESRD) or dialysis treatment, accounting for more than 40% of all patients with ESRD or receiving dialysis. Developing new therapeutics to prevent the transition to ESRD or dialysis treatment requires an understanding of the pathophysiology of DKD and an appropriate animal model for drug efficacy studies. In this study, we investigated the pathophysiology of diabetic kidney disease with type 2 diabetes in uninephrectomized db\/db mice. In addition, the nephrectomized db\/db mice from 10 weeks to 42 weeks were used to assess the efficacy of long-term administration of the angiotensin-II\u2013receptor antagonist losartan. The blood and urinary biochemical parameters and the blood pressure which is a main pharmacological endpoint of the losartan therapy, were periodically measured. And at the end, histopathological analysis was performed. Uninephrectomized db\/db mice clearly developed obesity and hyperglycemia from young age. Furthermore, they showed renal pathophysiological changes, such as increased urinary albumin-creatinine ratio (UACR) (the peak value 3104\u00b1986 in 40-week-old mice), glomerular hypertrophy and increased fibrotic areas in the tubulointerstitial tubules. The blood pressure in the losartan group was significantly low compared to the normotensive Vehicle group. However, as expected, Losartan suppressed the increase in UACR (829\u00b1500) indicating the medication was sufficient, but the histopathological abnormalities including tubular interstitial fibrosis did not improve. These results suggest that the uninephrectomized db\/db mice are useful as an animal model of the severe DKD indicated by the comparison of the efficacy of losartan in this model with the efficacy of losartan in clinical practice.<\/jats:p>","DOI":"10.33549\/physiolres.934784","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T13:48:08Z","timestamp":1652363288000},"page":"209-217","source":"Crossref","is-referenced-by-count":13,"title":["Pathophysiological Analysis of Uninephrectomized db\/db Mice as a Model of Severe Diabetic Kidney Disease"],"prefix":"10.33549","author":[{"given":"M","family":"Maekawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Maekawa","sequence":"additional","affiliation":[{"name":"Biological\/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan. tatsuya.maekawa@jt.com"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Sasase","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Takagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Takeuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Kitamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Nakagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Toyoda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Konishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Ohta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"19169","published-online":{"date-parts":[[2022,4,30]]},"reference":[{"key":"ref0","doi-asserted-by":"publisher","unstructured":"1.\tCoresh J. Update on the Burden of CKD. J Am Soc Nephrol 2017;28:1020-1022. https:\/\/doi.org\/10.1681\/ASN.2016121374","DOI":"10.1681\/asn.2016121374"},{"key":"ref1","doi-asserted-by":"publisher","unstructured":"2.\tSaran R, Robinson B, Abbott KC, Agodoa LYC, Bhave N, Bragg-Gresham J, Balkrishnan R, Dietrich X, Eckard A, Eggers PW, Gaipov A, Gillen D, Gipson D, Hailpern SM, Hall YN, Han Y, He K, Herman W, Heung M, et al. US Renal Data System 2017 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis 2018;71:A7. https:\/\/doi.org\/10.1053\/j.ajkd.2018.01.002","DOI":"10.1053\/j.ajkd.2018.01.002"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"3.\tSaran R, Robinson B, Abbott KC, Agodoa LYC, Bragg-Gresham J, Balkrishnan R, Bhave N, Dietrich X, Ding Z, Eggers PW, Gaipov A, Gillen D, Gipson D, Gu H, Guro P, Haggerty D, Han Y, He K, Herman W, et al. US Renal Data System 2018 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis 2019;73:A7-A8. https:\/\/doi.org\/10.1053\/j.ajkd.2019.01.001","DOI":"10.1053\/j.ajkd.2019.01.001"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"4.\tAndrade-Oliveira V, Foresto-Neto O, Watanabe IKM, Zatz R, Camara NOS. Inflammation in Renal Diseases: New and Old Players. Front Pharmacol 2019;10:1192. https:\/\/doi.org\/10.3389\/fphar.2019.01192","DOI":"10.3389\/fphar.2019.01192"},{"key":"ref4","unstructured":"5.\tJapanese Society of Nephrology: Clinical Practice Guidebook for Diagnosis and Treatment of Chronic Kidney Disease 2012. Tokyo Igakusha. Tokyo, 2012."},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"6.\tSato Y, Yanagita M. Functional heterogeneity of resident fibroblasts in the kidney. Proc Jpn Acad Ser B Phys Biol Sci 2019;95:468-478. https:\/\/doi.org\/10.2183\/pjab.95.033","DOI":"10.2183\/pjab.95.033"},{"key":"ref6","unstructured":"7.\tNational Kidney F. K\/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1-266"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"8.\tAndrassy KM. Comments on 'KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease'. Kidney Int 2013;84:622-623. https:\/\/doi.org\/10.1038\/ki.2013.243","DOI":"10.1038\/ki.2013.243"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"9.\tBohle A, von Gise H, Mackensen-Haen S, Stark-Jakob B. The obliteration of the postglomerular capillaries and its influence upon the function of both glomeruli and tubuli. Functional interpretation of morphologic findings. Klin Wochenschr 1981;59:1043-1051. https:\/\/doi.org\/10.1007\/BF01747747","DOI":"10.1007\/bf01747747"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"10.\tYamaguchi J, Tanaka T, Nangaku M. Recent advances in understanding of chronic kidney disease. F1000Res 2015;4. https:\/\/doi.org\/10.12688\/f1000research.6970.1","DOI":"10.12688\/f1000research.6970.1"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"11.\tNitta K, Abe M, Masakane I, Hanafusa N, Taniguchi M, Hasegawa T, Nakai S, Wada A, Hamano T, Hoshino J, Joki N, Goto S, Wakasugi M, Yamamoto K, Nakamoto H, Maeno K, Kawata T, Oyama C, Seino K, Sato T, Sato S, Ito M, Kazama J, Ueda A, Saito O, Ando T, Ogawa T, Kumagai H, Terawaki H, Ando R, Abe M, Kashiwagi T, Hamada C, Shibagaki Y, Hirawa N, Shimada H, Ishida Y, Yokoyama H, Miyazaki R, Fukasawa M, Kamijyo Y, Matsuoka T, Kato A, Mori N, Ito Y, Kasuga H, Koyabu S, Arimura T, Hashimoto T, Inaba M, Hayashi T, Yamakawa T, Nishi S, Fujimori A, Yoneda T, Negi S, Nakaoka A, Ito T, Sugiyama H, Masaki T, Nitta Y, Okada K, Yamanaka M, Kan M, Ota K, Tamura M, Mitsuiki K, Ikeda Y, Nishikido M, Miyata A, Tomo T, Fujimoto S, Nosaki T, Oshiro Y, on behalf of the Japanese Society for Dialysis Therapy Renal Data Registry C. Annual dialysis data report 2018, JSDT Renal Data Registry: dialysis fluid quality, hemodialysis and hemodiafiltration, peritoneal dialysis, and diabetes. Renal Replacement Therapy 2020;6:51. https:\/\/doi.org\/10.1186\/s41100-020-00290-z","DOI":"10.1186\/s41100-020-00286-9"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"12.\tNinomiya T, Kiyohara Y, Kubo M, Yonemoto K, Tanizaki Y, Doi Y, Hirakata H, Iida M. Metabolic syndrome and CKD in a general Japanese population: the Hisayama Study. Am J Kidney Dis 2006;48:383-391. https:\/\/doi.org\/10.1053\/j.ajkd.2006.06.003","DOI":"10.1053\/j.ajkd.2006.06.003"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"13.\tZhang X, Lerman LO. The metabolic syndrome and chronic kidney disease. Transl Res 2017;183:14-25. https:\/\/doi.org\/10.1016\/j.trsl.2016.12.004","DOI":"10.1016\/j.trsl.2016.12.004"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"14.\tKim Y, Park CW. Mechanisms of Adiponectin Action: Implication of Adiponectin Receptor Agonism in Diabetic Kidney Disease. Int J Mol Sci 2019;20:1782. https:\/\/doi.org\/10.3390\/ijms20071782","DOI":"10.3390\/ijms20071782"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"15.\tWang YM, Wang Y, Harris DCH, Alexander SI, Lee VWS. Adriamycin nephropathy in BALB\/c mice. Curr Protoc Immunol 2015;108:15.28.1-15.28.6. https:\/\/doi.org\/10.1002\/0471142735.im1528s108","DOI":"10.1002\/0471142735.im1528s108"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"16.\tPerse M, Veceric-Haler Z. Cisplatin-Induced Rodent Model of Kidney Injury: Characteristics and Challenges. Biomed Res Int 2018;2018:1462802. https:\/\/doi.org\/10.1155\/2018\/1462802","DOI":"10.1155\/2018\/1462802"},{"key":"ref16","unstructured":"17.\tKujal P, Vernerova Z. [5\/6 nephrectomy as an experimental model of chronic renal failure and adaptation to reduced nephron number]. Cesk Fysiol 2008;57:104-109."},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"18.\tDendooven A, Ishola DA, Jr., Nguyen TQ, Van der Giezen DM, Kok RJ, Goldschmeding R, Joles JA. Oxidative stress in obstructive nephropathy. Int J Exp Pathol 2011;92:202-210. https:\/\/doi.org\/10.1111\/j.1365-2613.2010.00730.x","DOI":"10.1111\/j.1365-2613.2010.00730.x"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"19.\tSharma K, McCue P, Dunn SR. Diabetic kidney disease in the db\/db mouse. Am J Physiol Renal Physiol 2003;284:F1138-1144. https:\/\/doi.org\/10.1152\/ajprenal.00315.2002","DOI":"10.1152\/ajprenal.00315.2002"},{"key":"ref19","unstructured":"20.\tNinichuk V, Kulkarni O, Clauss S, Anders H. Tubular atrophy, interstitial fibrosis, and inflammation in type 2 diabetic db\/db mice. An accelerated model of advanced diabetic nephropathy. Eur J Med Res 2007;12:351-355"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"21.\tDalb\u00f8ge LS, Almholt DL, Neerup TS, Vassiliadis E, Vrang N, Pedersen L, Fosgerau K, Jelsing J. Characterisation of age-dependent beta cell dynamics in the male db\/db mice. PLoS One 2013;8:e82813. https:\/\/doi.org\/10.1371\/journal.pone.0082813","DOI":"10.1371\/journal.pone.0082813"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"22.\tTrevisan R, Dodesini AR. The Hyperfiltering Kidney in Diabetes. Nephron 2017;136:277-280. https:\/\/doi.org\/10.1159\/000448183","DOI":"10.1159\/000448183"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"23.\tBreyer MD, Qi Z. Better nephrology for mice--and man. Kidney Int 2010;77:487-489. https:\/\/doi.org\/10.1038\/ki.2009.544","DOI":"10.1038\/ki.2009.544"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"24.\tBarsanti JA: Urinary Disorders. In: Small Animal Clinical Diagnosis by Laboratory Methods. M Willard, H Tvedten (eds), Saunders, Philadelphia, PA, U.S.A., 2012, pp 126-155.","DOI":"10.1016\/b978-1-4377-0657-4.00007-7"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"25.\tSimonds SE, Pryor JT, Ravussin E, Greenway FL, Dileone R, Allen AM, Bassi J, Elmquist JK, Keogh JM, Henning E, Myers MG, Jr., Licinio J, Brown RD, Enriori PJ, O'Rahilly S, Sternson SM, Grove KL, Spanswick DC, Farooqi IS, Cowley MA. Leptin mediates the increase in blood pressure associated with obesity. Cell 2014;159:1404-1416. https:\/\/doi.org\/10.1016\/j.cell.2014.10.058","DOI":"10.1016\/j.cell.2014.10.058"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"26.\tHirsch GE, Heck TG. Inflammation, oxidative stress and altered heat shock response in type 2 diabetes: the basis for new pharmacological and non-pharmacological interventions. Arch Physiol Biochem 2019:1-15. https:\/\/doi.org\/10.1080\/13813455.2019.1687522","DOI":"10.1080\/13813455.2019.1687522"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"27.\tLong KR, Rbaibi Y, Gliozzi ML, Ren Q, Weisz OA. Differential kidney proximal tubule cell responses to protein overload by albumin and its ligands. Am J Physiol Renal Physiol 2020;318:F851-F859. https:\/\/doi.org\/10.1152\/ajprenal.00490.2019","DOI":"10.1152\/ajprenal.00490.2019"},{"key":"ref27","unstructured":"28.\tSato Y, Yanagita M. [Current concept in renal fibrosis]. Nihon Jinzo Gakkai Shi 2015;57:1187-1192"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"29.\tHe P, Li D, Zhang B. Losartan attenuates renal interstitial fibrosis and tubular cell apoptosis in a rat model of obstructive nephropathy. Mol Med Rep 2014;10:638-644. https:\/\/doi.org\/10.3892\/mmr.2014.2304","DOI":"10.3892\/mmr.2014.2304"},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"30.\tYao Y, Li Y, Zeng X, Ye Z, Li X, Zhang L. Losartan Alleviates Renal Fibrosis and Inhibits Endothelial-to-Mesenchymal Transition (EMT) Under High-Fat Diet-Induced Hyperglycemia. Front Pharmacol 2018;9:1213. https:\/\/doi.org\/10.3389\/fphar.2018.01213","DOI":"10.3389\/fphar.2018.01213"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"31.\tTanamas SK, Saulnier PJ, Fufaa GD, Wheelock KM, Weil EJ, Hanson RL, Knowler WC, Bennett PH, Nelson RG. Long-term Effect of Losartan on Kidney Disease in American Indians With Type 2 Diabetes: A Follow-up Analysis of a Randomized Clinical Trial. Diabetes Care 2016;39:2004-2010. https:\/\/doi.org\/10.2337\/dc16-0795","DOI":"10.2337\/dc16-0795"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"32.\tLooker HC, Mauer M, Saulnier PJ, Harder JL, Nair V, Boustany-Kari CM, Guarnieri P, Hill J, Esplin CA, Kretzler M, Nelson RG, Najafian B. Changes in Albuminuria But Not GFR are Associated with Early Changes in Kidney Structure in Type 2 Diabetes. J Am Soc Nephrol 2019;30:1049-1059. https:\/\/doi.org\/10.1681\/ASN.2018111166","DOI":"10.1681\/asn.2018111166"}],"container-title":["Physiological Research"],"original-title":[],"language":"en","deposited":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T13:49:13Z","timestamp":1652363353000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.biomed.cas.cz\/physiolres\/pdf\/2022\/71_209.pdf"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,30]]},"references-count":32,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,4,30]]}},"URL":"https:\/\/doi.org\/10.33549\/physiolres.934784","relation":{},"ISSN":["1802-9973","0862-8408"],"issn-type":[{"value":"1802-9973","type":"electronic"},{"value":"0862-8408","type":"print"}],"subject":[],"published":{"date-parts":[[2022,4,30]]}}}