Studying the Roles of the Renin-Angiotensin System in Accelerating the Disease of High-Fat-Diet-Induced Diabetic Nephropathy in a db/db and ACE2 Double-Gene-Knockout Mouse Model

• Published in: International journal of molecular sciences Vol. 25; no. 1; p. 329
• Main Authors: Chen, Cheng-Yi, Lin, Meng-Wei, Xie, Xing-Yang, Lin, Cheng-Han, Yang, Chung-Wei, Wu, Pei-Ching, Liu, Dung-Huan, Wu, Chih-Jen, Lin, Chih-Sheng
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26.12.2023; MDPI
• Subjects: ACE inhibitors; Analysis; angiotensin converting enzyme II (ACE2); Cholesterol; chymase; Creatinine; Diabetes; Diabetic nephropathies; Diabetic nephropathy; Diet therapy; Enzymes; Genes; Glucose; high-fat-diet; Hyperglycemia; Inflammation; Insulin resistance; Kidney diseases; Mice; Obesity; Peptides; renin angiotensin system; Type 2 diabetes; Taiwan; high-fat-diet; renin angiotensin system; diabetic nephropathy; angiotensin converting enzyme II (ACE2); chymase
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25010329

Diabetic nephropathy (DN) is a crucial metabolic health problem. The renin-angiotensin 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.