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The renin\u2013angiotensin system (RAS) is well known to play an important role in DN. Abnormal RAS activity can cause the over-accumulation of angiotensin II (Ang II). Angiotensin-converting enzyme inhibitor (ACEI) administration has been proposed as a therapy, but previous studies have also indicated that chymase, the enzyme that hydrolyzes angiotensin I to Ang II in an ACE-independent pathway, may play an important role in the progression of DN. Therefore, this study established a model of severe DN progression in a db\/db and ACE2 KO mouse model (db and ACE2 double-gene-knockout mice) to explore the roles of RAS factors in DNA and changes in their activity after short-term (only 4 weeks) feeding of a high-fat diet (HFD) to 8-week-old mice. The results indicate that FD-fed db\/db and ACE2 KO mice fed an HFD represent a good model for investigating the role of RAS in DN. An HFD promotes the activation of MAPK, including p-JNK and p-p38, as well as the RAS signaling pathway, leading to renal damage in mice. Blocking Ang II\/AT1R could alleviate the progression of DN after administration of ACEI or chymase inhibitor (CI). Both ACE and chymase are highly involved in Ang II generation in HFD-induced DN; therefore, ACEI and CI are potential treatments for DN.<\/jats:p>","DOI":"10.3390\/ijms25010329","type":"journal-article","created":{"date-parts":[[2023,12,26]],"date-time":"2023-12-26T04:40:44Z","timestamp":1703565644000},"page":"329","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Studying the Roles of the Renin\u2013Angiotensin System in Accelerating the Disease of High-Fat-Diet-Induced Diabetic Nephropathy in a db\/db and ACE2 Double-Gene-Knockout Mouse Model"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3634-9661","authenticated-orcid":false,"given":"Cheng-Yi","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Hsinchu 300, Taiwan"},{"name":"MacKay Junior College of Medicine, Nursing and Management, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Wei","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing-Yang","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Han","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Wei","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu 300, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Ching","family":"Wu","sequence":"additional","affiliation":[{"name":"Doctoral Degree Program of Biomedical Science and Engineering, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan"},{"name":"Department of Chinese Medicine, China Medical University Hospital, Taichung 404, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dung-Huan","family":"Liu","sequence":"additional","affiliation":[{"name":"Doctoral Degree Program of Biomedical Science and Engineering, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan"},{"name":"Department of Physical Medicine and Rehabilitation, China Medical University Hospital, Taichung 404, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Jen","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei 100, Taiwan"},{"name":"Division of Medicine, College of Medicine, Taipei Medical University, Taipei 100, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1140-7933","authenticated-orcid":false,"given":"Chih-Sheng","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan"},{"name":"Doctoral Degree Program of Biomedical Science and Engineering, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan"},{"name":"Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"177","DOI":"10.5001\/omj.2017.34","article-title":"Diabetes Mellitus: A Local and Global Public Health Emergency!","volume":"32","year":"2017","journal-title":"Oman Med. 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