Effect of fetuin-A on adenine-induced chronic kidney disease model in male rats

Document Type : Original Article


Physiology Department, Faculty of Medicine, Zagazig university, Sharqia government, Egypt



Objective(s): This study aimed to investigate the possible effects of fetuin-A on an adenine-induced chronic kidney disease (CKD) model in male rats. 
Materials and Methods: Rats were divided into three groups: group A included rats fed a normal diet; group B included rats fed a normal diet with 220 mg/kg adenine daily for 21 days; group C included rats fed a normal diet with 220 mg/kg adenine daily for 21 days and intraperitoneally administered with 5 mg\kg fetuin-A every other day for 2 weeks. Serum samples were assayed for serum creatinine, urea, sodium, potassium, calcium, phosphorus, tumor necrosis factor (TNF), interleukin-6 (IL-6), and estimated glomerular filtration rate (eGFR), and immunohistochemical staining was performed.
Results: Group B showed a significant increase in serum creatinine, urea, phosphorus, potassium, TNF, and IL-6 and a significant decrease in serum sodium, calcium, and eGFR compared with group A. Regarding immunohistochemistry, group B showed increased apoptosis. In group C, fetuin-A reduced the urea, creatinine, and phosphorus levels, and in group C, fetuin-A decreased inflammation and apoptosis by reduction of caspase-3 staining.
Conclusion: Fetuin-A improved kidney function in CKD due to its anti-inflammatory and anti-fibrotic role.


1. Mandal A, Patra A, Mandal S, Roy S, Mahapatra SD .Therapeutic potential of different commercially available synbiotic on acetaminophen-induced uremic rats. Clin Exp Nephrol 2015; 19: 168-177.
2. Ali BH, Al-Husseni I, Beegam S, Al-Shukaili A, Nemmar A, Schierling S, et al. Effect of gum arabic on oxidative stress and inflammation in adenine-induced chronic renal failure in rats. PLoS One. 2013; 8:e55242.
3. Kettler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH, Böhm R, et al. Cardiovascular mortality in patients on dialysis: A cross-sectional study. The Lancet 2003; 361:827-833.
4. Wojtysiak-Duma B, Malecha Jędraszek A, Burska A, Duma D, Donica H. Serum fetuin-A levels in patients with type 2 diabetes mellitus. Ann UMCS Sect DDD 2010; 2:93-99.
5. Jahnen-Dechent W, Heiss A, Schäfer C, Ketteler M. Fetuin-A regulation of calcified matrix metabolism. Circ Res 2011; 108:1494-1499.
6. Mattinzoli D, Ikehata M, Tsugawa K, Alfieri CM, Dongiovanni P, Trombetta E,et al. FGF23 and Fetuin-A interaction in the liver and in the circulation. Int J Biol Sci 2018; 14: 586-598.
7. Schafer C, Heiss A, Schwarz A, Westenfeld R, Ketteler M, Floege J, et al. The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest 2003; 112: 357–366.
8. Li W, Zhu S, Li J, Huang Y, Zhou R, Fan X, Yang H, et al. A hepatic protein, fetuin-A, occupies a protective role in lethal systemic inflammation. PLoS ONE 2011;6:18-24.
9. Sindhu S, Akhter N, Shenouda S, Wilson A, Ahmad R. Plasma fetuin-A/α2-HS-glycoprotein correlates negatively with inflammatory cytokines, chemokines and activation biomarkers in individuals with type-2 diabetes. BMC Immunology 2016; 17:33.
10. Altunts A, Yigit A, Inal S, Kidir V, Basri H, MehmentS .The relationship between fetuin A level and fetuin gene polymorphism in hemodialysis patients. Biom Res 2017; 28:495-502.
11. Ossareh S,Marghoob B, BayatR .Relationship between fetuin A and vascular or valvular calcification in Hemodialysis. J Clin Nephrol 2019;3: 001–011.
12. Mohamed A, Mohammed N, Abdallah A, Hassan M ,Kamel S. Associations of fetuin-A level with vascular disease in hemodialysis patients with or without type II diabetes mellitus. Egypt J Intern Med 2013;25: 218.224.
13. Mutluay R, Konca Değertekin C, Işıktaş Sayılar E, et al .Serum fetuin-A is associated with the components of MIAC (malnutrition, inflammation, atherosclerosis, and calcification) syndrome in different stages of chronic kidney disease. Turk J Med Sci 2019; 49:327-335. 
14. Saad E, El-Gayar, H, El-Demerdash R, Radwan. Frankincense administration antagonizes adenine-induced chronic renal failure in rats. Pharmacogn Mag 2018; 14:634-640. 
15. Rahman A, Yamazaki D, Sufiun A, Kitada K, Hitomi H, Nakano D, et al. A novel approach to adenine-induced chronic kidney disease associated anemia in rodents. PLoS One 2018;13:e0192531.
16. Ombrellino M, Wang H, Yang H. Fetuin, a negative acute phase protein, attenuates TNF synthesis and the innate inflammatory response to to carrageenan. Shock 2001;15:181-185.
17. Liu YQ, Duan XL, Chang YZ, Wang HT, Qian ZM. Molecular analysis of increased iron status in moderately exercised rats. Mol Cell Biochem 2006; 282:117–123.
18. Murray, R.L.  Creatinine In: Clinical Chemistry; Theory, Analysis and Correlation, Kaplan, L.A. and A.J. Pesce (Eds.). CV Mosby Co., St. Louis,1984, 1247-1253.
19. Kaplan, A. and Glucose, K. ClinChem. The CV Mosby Co., St Louis, Toronto, Princeton, 1984, 436. 
20. Henry RJ. et al. Clin. Chem., Harper & Row New York, Sec. Edit.1974; 643.
21. Robertson WG, Marshall RW. Calcium measurements in serum and plasma total and ionized. CRC Crit Rev Clin Lab Sci 1979;11:271-305.
22. Bansal VK, Walker HK, Hall WD, Hurst JW. Serum inorganic phosphorus. Clinical methods: The history, physical, and laboratory examinations. 3rd edition. Boston: Butterworths; 1990. 
23. Croft M, Duan W, Choi H, Eun S, Madireddi S, Mehta A. TNF superfamily in inflammatory disease: Translating basic insights. Trends Immunol 2012;33: 144–152.
24. Juhaz K, BuzásK, DudaE. Importance of reverse signaling of the TNF superfamily in immune regulation. Expert Rev Clin Immunol 2013; 9: 335-348.
25. Song XY, Gu M, Jin WW, Klinman DM, Wahl SM. Plasmid DNA encoding transforming growth factor-beta 1 suppresses chronic disease in a streptococcal cell wall-induced arthritis model. J Clin Invest 1998;101:2615-2621.
26. Besseling PJ, Pieters TT, Nguyen IT, de Bree PM, Willekes N, Dijk AH, et al. A plasma creatinine- and urea-based equation to estimate glomerular filtration rate in rats. Am J Physiol Renal Physiol  2021;320:F518-F524.
27. Aydogan A, Kocer G, Ozmen O, Kocer M., Onal L, Koskan O. Immunohistochemical expression of caspase-3, caspase-5, caspase-7 and apoptotic protease-activating factor-1 (APAF-1) in the liver and kidney of rats exposed to zoledronic acid (ZOL) and basic fibroblast growth factor (bFGF). Vet Q 2014; 34:137-142.
28. Feng M, Dipetrillo K. Non-invasive Blood Pressure Measurement in Mice. Methods Mol Biol 2009;573:45-55.
29. Kurtz TW, Griffin KA, Bidani AK, Davisson RL, Hall JE. Recommendations for blood pressure measurement in humans and experimental animals. Arterioscler Thromb Vasc Biol 2005;25:e22-33
30. Komsa-Penkova RS, Golemanov GM, Radionova ZV, Tonchev PT, Iliev SD, Penkov VV. Fetuin-A-Alpha2-Heremans-Schmid glycoprotein: From structure to a novel marker of chronic diseases part 1.fetuin-a as a calcium chaperone and inflammatory marker. J Biomed Clin Res 2018; 10: 90–97.
31. Komaba H, Masafumi F. “Fetuin–mineral complex: A new potential biomarker for vascular calcification?” Kidney Int 2009; 75:874-876.
32. Gluba-Brzózka A, Michalska-Kasiczak M, Franczyk-Skóra B, Nocun M, Banach M, Rysz J. Markers of increased cardiovascular risk in elderly patients with chronic kidney disease: A preliminary study. Lipids Health Dis 2016;15:22
33. Cai H, Su S, Li Y, Zeng H, Zhu Z, Guo J. Protective effects of Salvia miltiorrhiza on adenine‑induced chronic renal failure by regulating the metabolic profiling and modulating the NADPH oxidase/ROS/ERK and TGF‑β/Smad signaling pathways. J Ethnopharmacol 2018; 212:15365.
34. DiwanV, Brown L, Gobe GC. Adenine-induced chronic kidney disease in rats. Nephrology 2017; 23: 5-11.
35. Tormanen S, Porsti I, Lakkisto P, Tikkanen I, Niemela O, Paavonen T. Endothelin A receptor blocker and calcimimetic in the adenine rat model of chronic renal insufficiency. BMC Nephrol 2017;18:323.
36. Wang J, Wang F, Yun H, Zhang H, Zhang Q. Effect and mechanism of fucoidan derivatives from Laminaria japonica in experimental adenine‑induced chronic kidney disease. J Ethnopharmacol 2012; 139:807‑813
37. Muñoz Abellán C, Mangold-Gehring S, Micus S, Beddies G, Moritz A, Hartmann E, et al. A novel model of chronic kidney disease in rats: Dietary adenine in combination with unilateral nephrectomy. Kidney Dis 2019;3:135-143.
38. Ponder KG, Boise LH. The prodomain of caspase-3 regulates its own removal and caspase activation. Cell Death Discov 2019;5:56.
39. Yang B, Lan S, Dieudé M, Sabo-Vatasescu JB, Karakeussian-Rimbaud A, Turgeon J, et al. Caspase-3 is a pivotal regulator of microvascular rarefaction and renal fibrosis after ischemia-reperfusion injury. J Am Soc Nephrol 2018;29:1900-1916.
40. Zhang P, Shen H, Huang J, Wang H, Zhang B, Zhou R et al. Intraperitoneal administration of fetuin-A attenuates D-galactosamine/lipopolysaccharide-induced liver failure in mouse. Dig Dis Sci. 2014;59:1789-1797. 
41. Kebapcilar L, Bilgrir O, Cetinkaya E, Akyol M, Bilgrir F, Bozkaya G. The effect of Helicobacter pylori eradication on macrophage migration inhibitory factor, C-reactive protein and fetuin-a levels. Clinics 2010; 65:799-802.
42. Wang HE, Sama A. Anti-inflammatory role of fetuin-an in injury and infection. Curr Mol Med 2012;12:625-633.
43. Karabag T, Kucuk E, Tekin İ, Sayin M, Gursoy Y, Aydin M. Relationship of fetuin-A with restenosis in patients who underwent revascularization. J Lab Med 2016; 40:43-48.
44. Zhou Y, Yang S, Zhang P. Effect of exogenous Fetuin-A on TGF-β/smad signaling in hepatic stellate cells. Biomed Res Int 2016;2016:8462615.
45. Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev 2006; 86:747-803. 
46. Hodgin JB, Bitzer M, Wickman L, Afshinnia F, Wang SQ, O’Connor Ch, et al. Glomerular aging and focal global glomerulosclerosis: a podometric perspective. J Am Soc Nephrol 2015; 26: 3162-3178.
47. Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med 1998; 339:1448–1456.
48. Turgut F, Yaprak M, Tokmak F. Pathophysiological insights of hypertension in patients with chronic kidney disease. Resis Hypertens Chronic Kid Dis 2017; 127-137. 
49. Benz K, Hilgers K, Daniel C, Amann K. Vascular calcification in chronic kidney disease: The role of inflammation. Int J  Nephrol 2018;2018:4310379.
50. Rattazzi M, Bertacco E, Puato M, Faggin E, Pauletto P. Hypertension and vascular calcification. J Hypertens 2012;30:1885-1893.
51. Afsar C, Yurdaku S, Muderrisoglu C, Demir B, Aslan A, Aral H. Association of serum fetuin A levels with heart valve calcification and other biomarkers of inflammation among persons with acute coronary syndrome. Clin Invest Med 2012;35: 206-215.
52. Chen H, Chiu Y, Hsu S, Pai M, Yang J, Peng Y. Relationship between Fetuin A, vascular calcification and fracture risk in dialysis patients. Nephrol Dial Transplant 2016; 31:I530-I530.
53. Holt SG, Smith ER. Fetuin-A-containing calciprotein particles in mineral tracking and vascular disease. Nephrol Dial Transplant 2016; 31: 1583–1587.
54. Cuspidi C, Sala C. Is fetuin-A a biomarker of preclinical atherosclerosis in essential hypertension. Hypertens Res 2013; 36: 104-106.
55. Ford ML, Tomlinson LA, Smith ER, Rajkumar C, Holt SG. Fetuin-A is an independent determinant of change of aortic stiffness over 1year in non-diabetic patients with CKD stages 3 and 4. Nephrol Dial Transplant  2010; 25: 1853–1858.
56. Scialla JJ, Linda Kao WH, Crainicean C, Sozio SM, Oberai PC, Shafi T, et al. Biomarkers of vascular calcification and mortality in patients with ESRD. Clin J Am Soc Nephrol 2014; 9: 745-755.