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We investigated the action of the dual modulator, PTUPB, a soluble epoxide hydrolase and cyclooxygenase\u20102 inhibitor against diabetic nephropathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Sixteen\u2010week\u2010old type 2 diabetic and proteinuric obese ZSF1 rats were treated with vehicle, PTUPB or enalapril for 8\u00a0weeks. Measurements were made of epoxyeicosatrienoic acids, thromboxane B<jats:sub>2<\/jats:sub> (TBX<jats:sub>2<\/jats:sub>) and prostaglandin E2 (PGE<jats:sub>2<\/jats:sub>) in the kidney of these and lean ZSF1 rats along with their blood pressure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Result<\/jats:title><jats:p>Obese ZSF1 rats were diabetic with fivefold higher fasting blood glucose levels and markedly higher HbA1c levels compared with lean ZSF1 rats. PTUPB nor enalapril reduced fasting blood glucose or HbA1c but alleviated the development of diabetic nephropathy. In PTUPB\u2010treated obese ZSF1 rats, glomerular nephrin expression was preserved. Enalapril also alleviated diabetic nephropathy. Diabetic renal injury in obese ZSF1 rats was accompanied by renal inflammation with six to sevenfold higher urinary MCP\u20101 (CCR2) level and renal infiltration of CD\u201068 positive cells. PTUPB and enalapril significantly reduced urinary MCP\u20101 levels and renal mRNA expression of cytokines. Both PTUPB and enalapril lowered blood pressure. PTUPB but not enalapril decreased hyperlipidaemia and liver injury in obese ZSF1 rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Overall, the dual modulator PTUPB does not treat hyperglycaemia but can effectively alleviate hypertension, diabetic nephropathy, hyperlipidaemia and liver injury in type 2 diabetic rats. Our data further demonstrate that the renal actions of PTUPB are comparable with a current standard diabetic nephropathy treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15623","type":"journal-article","created":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T17:17:15Z","timestamp":1626196635000},"page":"4468-4484","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Multitarget molecule, PTUPB, to treat diabetic nephropathy in rats"],"prefix":"10.1111","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1952-351X","authenticated-orcid":false,"given":"Md. Abdul Hye","family":"Khan","sequence":"first","affiliation":[{"name":"Drug Discovery Center and Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Hee","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Entomology and Nematology and Comprehensive Cancer Center University of California  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott D.","family":"Barnett","sequence":"additional","affiliation":[{"name":"Drug Discovery Center and Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8079-3351","authenticated-orcid":false,"given":"Anna","family":"Stavniichuk","sequence":"additional","affiliation":[{"name":"Drug Discovery Center and Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1495-9509","authenticated-orcid":false,"given":"Wojciech K.","family":"Jankiewicz","sequence":"additional","affiliation":[{"name":"Drug Discovery Center and Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1408-8317","authenticated-orcid":false,"given":"Bruce D.","family":"Hammock","sequence":"additional","affiliation":[{"name":"Department of Entomology and Nematology and Comprehensive Cancer Center University of California  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9668-2899","authenticated-orcid":false,"given":"John D.","family":"Imig","sequence":"additional","affiliation":[{"name":"Drug Discovery Center and Cardiovascular Center Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,12]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2012070718"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14747"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14112"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1590\/2359-3997000000169"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2011.381"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/0897190016649551"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-11-0122"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200011233432103"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-014-3171-6"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gtc.2016.07.003"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2005.09916.x"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2006090990"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000116221.27079.ea"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14153"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20040125"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9020458"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M806315200"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-018-0072-9"},{"issue":"27","key":"e_1_2_12_20_1","first-page":"9072","article-title":"Non\u2010alcoholic fatty liver disease and type 2 diabetes mellitus: The liver disease of our age","volume":"20","author":"Firneisz G.","year":"2014","journal-title":"World Journal of Gastroenterology"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2003.00319.x"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0675-0"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1803999116"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2001.00777.x"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2005"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0b013e3282f1bb7d"},{"key":"e_1_2_12_27_1","first-page":"139","article-title":"Physiologic and pathophysiologic roles of cyclooxygenase\u20102 in the kidney","volume":"124","author":"Harris R. 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