Aqueous chicory seed extract ameliorates diabetic kidney damage via alteration of renal renin-angiotensin system (RAS) balance
Abstract
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.
1. Abbas A, Hadi K, Seied Amirhossein L, Ali G, Ahmad A, Zahra P, et al. Saffron has a therapeutic effect on nephropathy by regulating the expression of TLR4, S100A8, and HMGB1 genes and reducing oxidative stress in diabetic rats. Acta Biochim Iran. 2024;2(2). https://doi.org/10.18502/abi.v2i2.17934
2. Afonso LG, Silva-Aguiar RP, Teixeira DE, Alves SAS, Schmaier AH, Pinheiro AAS, et al. The angiotensin II/type 1 angiotensin II receptor pathway is implicated in the dysfunction of albumin endocytosis in renal proximal tubule epithelial cells induced by high glucose levels. Biochim Biophys Acta Gen Subj. 2024;1868(10):130684. https://doi.org/10.1016/j.bbagen.2024.130684
3. Maksimowski N, Williams VR, Scholey JW. Kidney ACE2 expression: Implications for chronic kidney disease. PLoS One. 2020;15(10):e0241534. https://doi.org/10.1371/journal.pone.0241534
4. Lv M, Chen Z, Hu G, Li Q. Therapeutic strategies of diabetic nephropathy: recent progress and future perspectives. Drug Discov Today. 2015;20(3):332-46. https://doi.org/10.1016/j.drudis.2014.10.007
5. Ruan Y, Yu Y, Wu M, Jiang Y, Qiu Y, Ruan S. The renin-angiotensin-aldosterone system: An old tree sprouts new shoots. Cell Signal. 2024;124:111426. https://doi.org/10.1016/j.cellsig.2024.111426
6. Ghahraman Abedi F, Sattar G-F. Dissecting the interaction between antiviral medication and diabetes mellitus. Acta Biochimica Iranica. 2024;2(3).
7. Zheng J, Hao H. Targeting renal damage: The ACE2/Ang-(1-7)/mas axis in chronic kidney disease. Cell Signal. 2024;124:111413. https://doi.org/10.1016/j.cellsig.2024.111413
8. Alenina N, dos Santos RAS. Chapter 21 - Angiotensin-(1-7) and Mas: A Brief History. In: Unger T, Steckelings UM, dos Santos RAS, editors. The Protective Arm of the Renin Angiotensin System (RAS). Boston: Academic Press; 2015. p. 155-9.
9. Dilauro M, Burns KD. Angiotensin-(1-7) and its effects in the kidney. Sci World J. 2009;9:522-35. https://doi.org/10.1100/tsw.2009.70
10. Oda Y, Nishi H, Nangaku M. Role of Inflammation in Progression of Chronic Kidney Disease in Type 2 Diabetes Mellitus: Clinical Implications. Semin Nephrol. 2023;43(3):151431. https://doi.org/10.1016/j.semnephrol.2023.151431
11. Amirhossein S, Amir K-H, Mojtaba F, Hadi K. Effect of aminoguanidine on plasminogen activator inhibitor-1 and receptor of advanced glycation endproduct in the liver of streptozotocin-induced diabetic rats. Acta Biochimica Iranica. 2023;1(4). https://doi.org/10.18502/abi.v1i4.14720
12. Usuelli V, La Rocca E. Novel therapeutic approaches for diabetic nephropathy and retinopathy. Pharmacol Res. 2015;98:39-44. https://doi.org/10.1016/j.phrs.2014.10.003
13. Chen S, Huan P, Ma T, Zhong Y, Ning D, Zhuang Y. Walnut peptide relieves hypertension and associated kidney and heart injury by regulating the renin-angiotensin-aldosterone system and intestinal microbiota. J Sci Food Agric. 2025;105(2):1170-84. https://doi.org/10.1002/jsfa.13907
14. Asgharpour M, Alirezaei A. Herbal antioxidants in dialysis patients: a review of potential mechanisms and medical implications. Ren Fail. 2021;43(1):351-61. https://doi.org/10.1080/0886022x.2021.1880939
15. Pourfarjam Y, Rezagholizadeh L, Nowrouzi A, Meysamie A, Ghaseminejad S, Ziamajidi N, et al. Effect of Cichorium intybus L. seed extract on renal parameters in experimentally induced early and late diabetes type 2 in rats. Ren Fail. 2017;39(1):211-21. https://doi.org/10.1080/0886022x.2016.1256317
16. Rezagholizadeh L, Pourfarjam Y, Nowrouzi A, Nakhjavani M, Meysamie A, Ziamajidi N, et al. Effect of Cichorium intybus L. on the expression of hepatic NF-κB and IKKβ and serum TNF-α in STZ− and STZ+ niacinamide-induced diabetes in rats. Diabetol Metab Syndr. 2016;8(1):11. https://doi.org/10.1186/s13098-016-0128-6
17. Ghamarian A, Abdollahi M, Su X, Amiri A, Ahadi A, Nowrouzi A. Effect of chicory seed extract on glucose tolerance test (GTT) and metabolic profile in early and late stage diabetic rats. DARU J Pharm Sci. 2012;20(1):56. https://doi.org/10.1186/2008-2231-20-56
18. Cushman DW, Cheung HS. Spectrophotometric assay and properties of the angiotensin-converting enzyme of rabbit lung. Biochem Pharmacol. 1971;20(7):1637-48. https://doi.org/10.1016/0006-2952(71)90292-9
19. Aragão DS, Cunha TS, Arita DY, Andrade MC, Fernandes AB, Watanabe IK, et al. Purification and characterization of angiotensin converting enzyme 2 (ACE2) from murine model of mesangial cell in culture. Int J Biol Macromol. 2011;49(1):79-84. https://doi.org/10.1016/j.ijbiomac.2011.03.018
20. Reznick AZ, Packer L. Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Methods Enzymol. 1994;233:357-63. https://doi.org/10.1016/s0076-6879(94)33041-7
21. Zimpelmann J, Kumar D, Levine DZ, Wehbi G, Imig JD, Navar LG, et al. Early diabetes mellitus stimulates proximal tubule renin mRNA expression in the rat. Kidney Int. 2000;58(6):2320-30. https://doi.org/10.1046/j.1523-1755.2000.00416.x
22. Kamiyama M, Zsombok A, Kobori H. Urinary angiotensinogen as a novel early biomarker of intrarenal renin–angiotensin system activation in experimental type 1 diabetes. J Pharmacol Sci. 2012;119(4):314-23. https://doi.org/10.1254/jphs.12076fp
23. Yang WX, Su K, Liao MC, Zhou J, Peng J, Hebert MJ, et al. Renal Tubule-Specific Angiotensinogen Deletion Attenuates SGLT2 Expression and Ameliorates Diabetic Kidney Disease in Murine Models of Type 1 Diabetes. Diabetes. 2025. https://doi.org/10.2337/db24-0553
24. Liu CX, Hu Q, Wang Y, Zhang W, Ma ZY, Feng JB, et al. Angiotensin-converting enzyme (ACE) 2 overexpression ameliorates glomerular injury in a rat model of diabetic nephropathy: a comparison with ACE inhibition. Mol Med. 2011;17(1-2):59. https://doi.org/10.1186/s10020-022-00482-9
25. Lakshmanan AP, Watanabe K, Thandavarayan RA, Sari FR, Harima M, Giridharan VV, et al. Telmisartan attenuates oxidative stress and renal fibrosis in streptozotocin induced diabetic mice with the alteration of angiotensin-(1–7) mas receptor expression associated with its PPAR-γ agonist action. Free Radic Res. 2011;45(5):575-84. https://doi.org/10.3109/10715762.2011.560149
26. Ueno A, Onishi Y, Mise K, Yamaguchi S, Kanno A, Nojima I, et al. Plasma angiotensin-converting enzyme 2 (ACE2) is a marker for renal outcome of diabetic kidney disease (DKD) (U-CARE study 3). BMJ Open Diabetes Res Care. 2024;12(3). https://doi.org/10.1136/bmjdrc-2024-004237
27. Soler M, Wysocki J, Ye M, Lloveras J, Kanwar Y, Batlle D. ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice. Kidney Int. 2007;72(5):614-23. https://doi.org/10.1038/sj.ki.5002539
28. Shao Y, He M, Zhou L, Yao T, Huang Y. Chronic angiotensin (1–7) injection accelerates STZ‐induced diabetic renal injury. Acta Pharmacol Sin. 2008;29(7):829-37. https://doi.org/10.1111/j.1745-7254.2008.00812.x
29. Chen R, Mukhin YV, Garnovskaya MN, Thielen TE, Iijima Y, Huang C, et al. A functional angiotensin II receptor-GFP fusion protein: evidence for agonist-dependent nuclear translocation. Am J Physiol Renal Physiol. 2000;279(3):F440-F8. https://doi.org/10.1152/ajprenal.2000.279.3.f440
30. Cumaoglu A, Stefek M, Bauer V, Ari N, Aricioglu A, Karasu C. Glycoxidative and nitrosative stress in kidney of experimental diabetic rats: effects of the prydoindole antioxidant stobadine. Neuro Endocrinol Lett. 2010;31(3):313-8.
31. Ozsoy N, Can A, Mutlu O, Akev N, Yanardag R. Oral zinc supplementation protects rat kidney tissue from oxidative stress in diabetic rats. Kafkas Univ Vet Fak. 2012;18:545-50. https://doi.org/10.9775/kvfd.2011.5650
32. Zhou X, Feng Y, Zhan Z, Chen J. Hydrogen sulfide alleviates diabetic nephropathy in a streptozotocin-induced diabetic rat model. J Biol Chem. 2014;289(42):28827-34. https://doi.org/10.1074/jbc.m114.596593
33. Ahmad S, Ahmad MFA, Alouffi S, Khan S, Khan M, Khan MWA, et al. Aldose reductase inhibitory and antiglycation properties of phytoconstituents of Cichorium intybus: Potential therapeutic role in diabetic retinopathy. Int J Biol Macromol. 2024;277(Pt 1):133816. https://doi.org/10.1016/j.ijbiomac.2024.133816
34. Mori J, Patel VB, Ramprasath T, Alrob OA, DesAulniers J, Scholey JW, et al. Angiotensin 1-7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity. Am J Physiol Renal Physiol. 2014;306(8):F812-21. https://doi.org/10.1152/ajprenal.00655.2013
35. Miyazaki M, Takai S. Tissue angiotensin II generating system by angiotensin-converting enzyme and chymase. Journal Pharmacol Sci. 2006;100(5):391-7. https://doi.org/10.1254/jphs.cpj06008x
2. Afonso LG, Silva-Aguiar RP, Teixeira DE, Alves SAS, Schmaier AH, Pinheiro AAS, et al. The angiotensin II/type 1 angiotensin II receptor pathway is implicated in the dysfunction of albumin endocytosis in renal proximal tubule epithelial cells induced by high glucose levels. Biochim Biophys Acta Gen Subj. 2024;1868(10):130684. https://doi.org/10.1016/j.bbagen.2024.130684
3. Maksimowski N, Williams VR, Scholey JW. Kidney ACE2 expression: Implications for chronic kidney disease. PLoS One. 2020;15(10):e0241534. https://doi.org/10.1371/journal.pone.0241534
4. Lv M, Chen Z, Hu G, Li Q. Therapeutic strategies of diabetic nephropathy: recent progress and future perspectives. Drug Discov Today. 2015;20(3):332-46. https://doi.org/10.1016/j.drudis.2014.10.007
5. Ruan Y, Yu Y, Wu M, Jiang Y, Qiu Y, Ruan S. The renin-angiotensin-aldosterone system: An old tree sprouts new shoots. Cell Signal. 2024;124:111426. https://doi.org/10.1016/j.cellsig.2024.111426
6. Ghahraman Abedi F, Sattar G-F. Dissecting the interaction between antiviral medication and diabetes mellitus. Acta Biochimica Iranica. 2024;2(3).
7. Zheng J, Hao H. Targeting renal damage: The ACE2/Ang-(1-7)/mas axis in chronic kidney disease. Cell Signal. 2024;124:111413. https://doi.org/10.1016/j.cellsig.2024.111413
8. Alenina N, dos Santos RAS. Chapter 21 - Angiotensin-(1-7) and Mas: A Brief History. In: Unger T, Steckelings UM, dos Santos RAS, editors. The Protective Arm of the Renin Angiotensin System (RAS). Boston: Academic Press; 2015. p. 155-9.
9. Dilauro M, Burns KD. Angiotensin-(1-7) and its effects in the kidney. Sci World J. 2009;9:522-35. https://doi.org/10.1100/tsw.2009.70
10. Oda Y, Nishi H, Nangaku M. Role of Inflammation in Progression of Chronic Kidney Disease in Type 2 Diabetes Mellitus: Clinical Implications. Semin Nephrol. 2023;43(3):151431. https://doi.org/10.1016/j.semnephrol.2023.151431
11. Amirhossein S, Amir K-H, Mojtaba F, Hadi K. Effect of aminoguanidine on plasminogen activator inhibitor-1 and receptor of advanced glycation endproduct in the liver of streptozotocin-induced diabetic rats. Acta Biochimica Iranica. 2023;1(4). https://doi.org/10.18502/abi.v1i4.14720
12. Usuelli V, La Rocca E. Novel therapeutic approaches for diabetic nephropathy and retinopathy. Pharmacol Res. 2015;98:39-44. https://doi.org/10.1016/j.phrs.2014.10.003
13. Chen S, Huan P, Ma T, Zhong Y, Ning D, Zhuang Y. Walnut peptide relieves hypertension and associated kidney and heart injury by regulating the renin-angiotensin-aldosterone system and intestinal microbiota. J Sci Food Agric. 2025;105(2):1170-84. https://doi.org/10.1002/jsfa.13907
14. Asgharpour M, Alirezaei A. Herbal antioxidants in dialysis patients: a review of potential mechanisms and medical implications. Ren Fail. 2021;43(1):351-61. https://doi.org/10.1080/0886022x.2021.1880939
15. Pourfarjam Y, Rezagholizadeh L, Nowrouzi A, Meysamie A, Ghaseminejad S, Ziamajidi N, et al. Effect of Cichorium intybus L. seed extract on renal parameters in experimentally induced early and late diabetes type 2 in rats. Ren Fail. 2017;39(1):211-21. https://doi.org/10.1080/0886022x.2016.1256317
16. Rezagholizadeh L, Pourfarjam Y, Nowrouzi A, Nakhjavani M, Meysamie A, Ziamajidi N, et al. Effect of Cichorium intybus L. on the expression of hepatic NF-κB and IKKβ and serum TNF-α in STZ− and STZ+ niacinamide-induced diabetes in rats. Diabetol Metab Syndr. 2016;8(1):11. https://doi.org/10.1186/s13098-016-0128-6
17. Ghamarian A, Abdollahi M, Su X, Amiri A, Ahadi A, Nowrouzi A. Effect of chicory seed extract on glucose tolerance test (GTT) and metabolic profile in early and late stage diabetic rats. DARU J Pharm Sci. 2012;20(1):56. https://doi.org/10.1186/2008-2231-20-56
18. Cushman DW, Cheung HS. Spectrophotometric assay and properties of the angiotensin-converting enzyme of rabbit lung. Biochem Pharmacol. 1971;20(7):1637-48. https://doi.org/10.1016/0006-2952(71)90292-9
19. Aragão DS, Cunha TS, Arita DY, Andrade MC, Fernandes AB, Watanabe IK, et al. Purification and characterization of angiotensin converting enzyme 2 (ACE2) from murine model of mesangial cell in culture. Int J Biol Macromol. 2011;49(1):79-84. https://doi.org/10.1016/j.ijbiomac.2011.03.018
20. Reznick AZ, Packer L. Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Methods Enzymol. 1994;233:357-63. https://doi.org/10.1016/s0076-6879(94)33041-7
21. Zimpelmann J, Kumar D, Levine DZ, Wehbi G, Imig JD, Navar LG, et al. Early diabetes mellitus stimulates proximal tubule renin mRNA expression in the rat. Kidney Int. 2000;58(6):2320-30. https://doi.org/10.1046/j.1523-1755.2000.00416.x
22. Kamiyama M, Zsombok A, Kobori H. Urinary angiotensinogen as a novel early biomarker of intrarenal renin–angiotensin system activation in experimental type 1 diabetes. J Pharmacol Sci. 2012;119(4):314-23. https://doi.org/10.1254/jphs.12076fp
23. Yang WX, Su K, Liao MC, Zhou J, Peng J, Hebert MJ, et al. Renal Tubule-Specific Angiotensinogen Deletion Attenuates SGLT2 Expression and Ameliorates Diabetic Kidney Disease in Murine Models of Type 1 Diabetes. Diabetes. 2025. https://doi.org/10.2337/db24-0553
24. Liu CX, Hu Q, Wang Y, Zhang W, Ma ZY, Feng JB, et al. Angiotensin-converting enzyme (ACE) 2 overexpression ameliorates glomerular injury in a rat model of diabetic nephropathy: a comparison with ACE inhibition. Mol Med. 2011;17(1-2):59. https://doi.org/10.1186/s10020-022-00482-9
25. Lakshmanan AP, Watanabe K, Thandavarayan RA, Sari FR, Harima M, Giridharan VV, et al. Telmisartan attenuates oxidative stress and renal fibrosis in streptozotocin induced diabetic mice with the alteration of angiotensin-(1–7) mas receptor expression associated with its PPAR-γ agonist action. Free Radic Res. 2011;45(5):575-84. https://doi.org/10.3109/10715762.2011.560149
26. Ueno A, Onishi Y, Mise K, Yamaguchi S, Kanno A, Nojima I, et al. Plasma angiotensin-converting enzyme 2 (ACE2) is a marker for renal outcome of diabetic kidney disease (DKD) (U-CARE study 3). BMJ Open Diabetes Res Care. 2024;12(3). https://doi.org/10.1136/bmjdrc-2024-004237
27. Soler M, Wysocki J, Ye M, Lloveras J, Kanwar Y, Batlle D. ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice. Kidney Int. 2007;72(5):614-23. https://doi.org/10.1038/sj.ki.5002539
28. Shao Y, He M, Zhou L, Yao T, Huang Y. Chronic angiotensin (1–7) injection accelerates STZ‐induced diabetic renal injury. Acta Pharmacol Sin. 2008;29(7):829-37. https://doi.org/10.1111/j.1745-7254.2008.00812.x
29. Chen R, Mukhin YV, Garnovskaya MN, Thielen TE, Iijima Y, Huang C, et al. A functional angiotensin II receptor-GFP fusion protein: evidence for agonist-dependent nuclear translocation. Am J Physiol Renal Physiol. 2000;279(3):F440-F8. https://doi.org/10.1152/ajprenal.2000.279.3.f440
30. Cumaoglu A, Stefek M, Bauer V, Ari N, Aricioglu A, Karasu C. Glycoxidative and nitrosative stress in kidney of experimental diabetic rats: effects of the prydoindole antioxidant stobadine. Neuro Endocrinol Lett. 2010;31(3):313-8.
31. Ozsoy N, Can A, Mutlu O, Akev N, Yanardag R. Oral zinc supplementation protects rat kidney tissue from oxidative stress in diabetic rats. Kafkas Univ Vet Fak. 2012;18:545-50. https://doi.org/10.9775/kvfd.2011.5650
32. Zhou X, Feng Y, Zhan Z, Chen J. Hydrogen sulfide alleviates diabetic nephropathy in a streptozotocin-induced diabetic rat model. J Biol Chem. 2014;289(42):28827-34. https://doi.org/10.1074/jbc.m114.596593
33. Ahmad S, Ahmad MFA, Alouffi S, Khan S, Khan M, Khan MWA, et al. Aldose reductase inhibitory and antiglycation properties of phytoconstituents of Cichorium intybus: Potential therapeutic role in diabetic retinopathy. Int J Biol Macromol. 2024;277(Pt 1):133816. https://doi.org/10.1016/j.ijbiomac.2024.133816
34. Mori J, Patel VB, Ramprasath T, Alrob OA, DesAulniers J, Scholey JW, et al. Angiotensin 1-7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity. Am J Physiol Renal Physiol. 2014;306(8):F812-21. https://doi.org/10.1152/ajprenal.00655.2013
35. Miyazaki M, Takai S. Tissue angiotensin II generating system by angiotensin-converting enzyme and chymase. Journal Pharmacol Sci. 2006;100(5):391-7. https://doi.org/10.1254/jphs.cpj06008x
| Files | ||
| Issue | Vol 3 No 2 (2025) | |
| Section | Original Articles | |
| Keywords | ||
| Diabetic nephropathy Renin-Angiotensin System; Angiotensinogen ACE ACE2 chicory seed extract | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Ardalani S, Babaei Khalili M, Nowrouzi A. Aqueous chicory seed extract ameliorates diabetic kidney damage via alteration of renal renin-angiotensin system (RAS) balance. ABI. 2025;3(2):90-100.
