Tehran University of Medical Sciences Acta Biochimica Iranica 0001-5261 3 2 2025 06 20 90 100 Samin Ardalani Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Masoumeh Babaei Khalili Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. Azin Nowrouzi Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran. 2025 07 02 2025 07 20 Objectives:  This study investigated the effects of aqueous chicory seed extract (CSE), metformin (Met), and aspirin (Asp) on the Renin-Angiotensin System (RAS) in healthy Wistar rats, as well as in early (NIA/STZ) and late-stage diabetes (STZ). Methods: Rats were divided into Control, NIA/STZ, and STZ groups. NIA/STZ rats received niacinamide/streptozotocin, while STZ rats received STZ to induce early and late diabetes stages. Subgroups received CSE (125 mg/kg), metformin (100 mg/kg), or aspirin (120 mg/kg). Measurements included mRNA levels of AGT, ACE, ACE2, activities of ACE and ACE2, levels of Ang II and Ang-(1-7), protein carbonyl content (PCC), nitric oxide (NO), and kidney collagen. Results: Late-stage diabetes (STZ) decreased AGT, ACE, and ACE2 mRNA, but increased ACE activity, Ang II, Ang-(1-7), the ACE/ACE2 ratio, PCC, and collagen. CSE increased AGT and ACE2 mRNA, decreased ACE activity, Ang II, the ACE/ACE2 ratio, and PCC. Metformin boosted AGT mRNA and reduced PCC and collagen. Aspirin lowered collagen. Early diabetes (NIA/STZ) decreased AGT, ACE2, and Ang-(1-7), while increasing ACE activity and Ang II levels. CSE increased AGT and Ang-(1-7), reducing Ang II and the Ang II/Ang-(1-7) ratio. Metformin reduced ACE mRNA and increased Ang-(1-7). CSE decreased reactive oxygen species (ROS) and improved Ang-(1-7) levels, especially in early stages. Both CSE and metformin helped reduce fibrosis. Conclusion:     Our findings suggest that CSE supports renal tissue repair in both early and late stages of T2D by increasing the levels of the protective peptide Ang-(1-7), respectively. https://abi.tums.ac.ir/index.php/abi/article/view/135 https://abi.tums.ac.ir/index.php/abi/article/download/135/108 https://abi.tums.ac.ir/index.php/abi/article/download/135/109