• KARTHICK N SRM medical college, SRM university
  • Poornima Kn ,SRM Medical college, SRM University
  • Saravanan A Srm Medical college, SRM University
  • Alwin D Srm Medical college, SRM University
  • Venkataraman P Srm Medical college, SRM University


Objectives: Chronic kidney disease (CKD) is a major clinical health problem as it is a systemic disorder that causes widespread organ damage
and it is related to significant morbidity and mortality. Numerous studies have shown that, cognitive dysfunction increase in prevalence, due to
increase in reactive oxygen species in CKD severity. Tau proteins are proteins that stabilize microtubules. Hyperphosphorylation of tau reduces its
ability to bind to microtubule causes dystabilization and production of neurofibrillary tangles (NFT) and neurodegeneration in the brain. Aberrant
hyperphosphorylation of tau is critical to the progression of neurodegeneration. Erythropoietin (EPO), a glycoprotein has been in clinical use for
millions of anemic patients, and some studies show it has a neuroprotective role. Till now studies on the level of tau protein phosphorylation in brain
regions of CKD-induced experimental animals and impact of EPO therapy are scarce. The aim of this study is to determine the impact of CKD and EPO
therapy on tau protein phosphorylation in brain regions of experimental rats.
Methods: This study was performed on 48 adult male Wistar rats. Two phases were conducted to find out the difference between simultaneous and
posttreatment of EPO. Phase I: 24 adult male Wistar rats were divided into 4 groups (6 animals each): Group 1: Control, Group 2: 0.75% of adenine
mixed diet for 4 weeks, Group 3: 0.75% of adenine mixed diet was given for 4 weeks and simultaneous administration of EPO (100 IU/kg btw, ip)
thrice weekly. Group 4: EPO alone (100 IU/Kg btw, ip) thrice per week. All the animals were sacrificed uniformly at the end of 4 weeks. In Phase II,
24 animals were maintained separately for 40 days experimental period and divided into 4 groups. Groups 1, 2, and 4 animals were treated as same
mentioned in Phase I. Group 3: For EPO posttreatment, adenine mixed diet was given for 4 weeks for chronic renal failure (CRF) induction. After the 4

week, EPO (100 IU/Kg btw.) was administered daily once for 12 days. At the end of the 40 days, all the animals were sacrificed uniformly. In both the
phases after the treatment period, the brain tissue was removed and samples were homogenized. Total tau protein and phosphorylated tau protein
expressions were analyzed by western blotting method.
Results: In results, both the total tau and phosphorylated tau protein levels were significantly increased all the brain regions of CRF-induced groups
when compared to control. In both simultaneous and posttreatment of EPO, the levels were retrieved.
Conclusion: This study proves that EPO supplementation has a promising role in neuroprotection by preventing abnormal phosphorylated tau
protein accumulation. This study also proves the clinical usefulness of EPO as a supplemental therapeutic agent in neurotoxicity.
Keywords: Chronic renal failure, Cognitive dysfunction, Hyperphosphorylation of tau protein, Erythropoietin.

Author Biographies

KARTHICK N, SRM medical college, SRM university

Assistant professor, Department of physiology,SRM Medical college,Potheri, Chennai.

Poornima Kn, ,SRM Medical college, SRM University
Assistant professor, Department of physiology,SRM Medical college,Potheri, Chennai.
Saravanan A, Srm Medical college, SRM University

Professor, SRM Medical college, SRM University,

Potheri, chennai

Alwin D, Srm Medical college, SRM University
veterinary officer, Srm Medical college, SRM University.
Venkataraman P, Srm Medical college, SRM University
Assistant professor, Department of medical research, SRM Medical college,Potheri, Chennai.


1. Ikeda R, Imai Y, Maruyama W, Mizoguchi K. Systemic disorders of
calcium dynamics in rats with adenine induced renal failure: Implication
for chronic ksidney disease related complications. Nephrology (Carlton)
2. Meyer TW, Hostetter TH. Uremia. N Engl J Med 2007;357(13):1316-25.
3. Babb AL, Ahmad S, Bergström J, Scribner BH. The middle molecule
hypothesis in perspective. Am J Kidney Dis 1981;1(1):46-50.
4. Vanholder R, De Smet R, Hsu C, Vogeleere P, Ringoir S. Uremic
toxicity: The middle molecule hypothesis revisited. Semin Nephrol
5. Sener G, Sakarcan A, Sehirli O, Ekshioglu-Demiralp E, Sener E, ErcanF,
et al. Chronic renal failure – induced multiple – organ injury in rats is
alleviated by the selective CysLT1 receptor antagonist montelukast.
Prostaglandins Other Lipid Mediat 2007;83(4):257-67.
6. Murray AM. Cognitive impairment in the aging dialysis and chronic
kidney disease populations: An occult burden. Adv Chronic Kidney Dis
7. Hailpern SM, Melamed ML, Cohen HW, Hostetter TH. Moderate
chronic kidney disease and cognitive function in adults 20 to 59 years
of age: Third National Health and Nutrition Examination Survey
(NHANES III). J Am Soc Nephrol 2007;18(7):2205-13.
8. Butterfield DA, Reed T, Newman SF, Sultana R. Roles of amyloid
β-peptide-associated oxidative stress and brain protein modifications in
the pathogenesis of Alzheimer’s disease and mild cognitive impairment.
Free Radic Biol Med 2007;43(5):658-77.
9. Alonso AC, Grundke-Iqbal I, Barra HS, Iqbal K. Abnormal hyper
phosphorylation of tau and the mechanism of Alzheimer neurofibrillary
degeneration: Sequestration of microtubule-associated proteins 1 and
2 and the disassembly of microtubules by the abnormal tau. Proc Natl
Acad Sci USA 1997;94(1):298-303.
10. Noble W, Pooler AM, Hanger DP. Advances in tau-based drug
discovery. Expert Opin Drug Discov 2011;6(8):797-810.
11. Castro-Alvarez JF, Gutierrez-Vargas J, Darnaudéry M,
Cardona-Gómez GP. ROCK inhibition prevents tau
hyperphosphorylation and p25/CDK5 increase after global cerebral
ischemia. Behav Neurosci 2011;125(3):465-72.
12. Taylor JP, Hardy J, Fischbeck KH. Toxic proteins in neurodegenerative
disease. Science 2002;296(5575):1991-15.
13. Gomez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC,
et al. Neuronal loss correlates with but exceeds neurofibrillary tangles
in Alzeimer’s disease. Eur J Biochem 1997;244:414-25.
14. Yang Y, Zhang J, Ma D, Zhang M, Hu S, Shao S, et al. Subcutaneous
administration of liraglutide ameliorates Alzheimer-associated tau
hyperphosphorylation in rats with type 2 diabetes. J Alzheimers Dis
15. Sirén AL, Ehrenreich H. Erythropoietin – A novel concept
for neuroprotection. Eur Arch Psychiatry Clin Neurosci
16. Mimic-Oka J, Simic T, Djukanovic L. Epoetin treatment improves red
blood cell and plasma antioxidant capacity in hemodialysis patients.
Ren Fail 2002;24(1):77-87.
17. Brines M, Cerami A. Discovering erythropoietin’s extrahematopoietic
functions: Biology and clinical promise. Kidney Int

18. Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuroprotection
involves cross-talk between Jak2 and NF-κB signalling cascades.
Nature 2001;412(6847):641-7.
19. Adamcio B, Sargin D, Stradomska A, Medrihan L, Gertler C, Theis F,
et al. Erythropoietin enhances hippocampal long-term potentiation and
memory. BMC Biol 2008;6:37.
20. Ali BH, Al-Salam S, Al Za’abi M, Waly MI, Ramkumar A, Beegam S,
et al. New model for adenine-induced chronic renal failure in mice,
and the effect of gum acacia treatment thereon: Comparison with rats.
J Pharmacol Toxicol Methods 2013;68(3):384-93.
21. Bagnis C, Beaufils H, Jacquiaud C, Adabra Y, Jouanneau C, Le
Nahour G, et al. Erythropoietin enhances recovery after cisplatininduced
the rat. Nephrol Dial Transplant

22. Lee DW, Kwak IS, Lee SB, Song SH, Seong EY, Yang BY, et al. Posttreatment
of erythropoietin and
nordihydroguaiaretic acid
from cisplatin-induced acute
renal failure in the rat. J

Sci 2009;24
23. Glowinski J, Iversen LL, Axelrod J. Storage and synthesis of
norepinephrine in the reserpine-treated rat brain. J Pharmacol Exp Ther
24. Krishnan AV, Kiernan MC. Neurological complications of chronic
kidney disease. Nat Rev Neurol 2009;5(10):542-51.
25. Chilcot J, Wellsted D, Vilar E, Farrington K. An association between
residual renal function and depression symptoms in haemodialysis
patients. Nephron Clin Pract 2009;113(2):c117-24.
26. Kliem V, Johnson RJ, Alpers CE, Yoshimura A, Couser WG, Koch KM,
et al. Mechanisms involved in the pathogenesis of tubulointerstitial
fibrosis in 5/6-nephrectomized rats. Kidney Int 1996;49(3):666-78.
27. Cleveland DW, Hwo SY, Kirschner MW. Physical and chemical
properties of purified tau factor and the role of tau in microtubule
assembly. J Mol Biol 1977;116(2):227-47.
28. Kosik KS. The molecular and cellular biology of tau. Brain Pathol
29. Mandelkow EM, Stamer K, Vogel R, Thies E, Mandelkow E. Clogging
of axons by tau, inhibition of axonal traffic and starvation of synapses.
Neurobiol Aging 2003;24(8):1079-85.
30. LaPointe NE, Morfini G, Pigino G, Gaisina IN, Kozikowski AP,
Binder LI, et al. The amino terminus of tau inhibits kinesin-dependent
axonal transport: Implications for filament toxicity. J Neurosci Res
31. Sergeant N, Delacourte A, Buée L. Tau protein as a differential biomarker
of tauopathies. Biochim Biophys Acta 2005;1739(2-3):179-97.
32. Avila J. Tau kinases and phosphatases: Commentary. J Cell Mol Med
33. Iqbal K, Grundke-Iqbal I. Alzheimer neurofibrillary degeneration:
Significance, etiopathogenesis, therapeutics and prevention: Alzheimer
review series. J Cell Mol Med 2009;12(1):38-55.
34. Barinaga M. What makes brain neurons run? Science
35. Sangkabutra T, Crankshaw DP, Schneider C, Fraser SF, Sostaric S,
Mason K, et al. Impaired K+ regulation contributes to exercise
limitation in end-stage renal failure. Kidney Int 2003;63(1):283-90.
36. Karthick N, Alwin D, Poornima KN, Chitra V, Saravanan A,
Balakrishnan D, et al. Neurobehavioral alterations and brain creatine
kinase system changes in chronic renal failure induced male wistar
rats: Impact of erythropoietin supplementation. J Bioequiv Availab
37. Aksenov M, Aksenova M, Butterfield DA, Markesbery WR. Oxidative
modification of creatine kinase BB in Alzheimer’s disease brain.
J Neurochem 2000;74(6):2520-7.
Asian J Pharm Clin Res, Vol 9, Issue 3, 2016, 392-397
Karthick et al.
38. Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC,
Cerami C, et al. Erythropoietin crosses the blood-brain barrier to
protect against experimental brain injury. Proc Natl Acad Sci USA
39. Zhang Y, Xiong Y, Mahmood A, Meng Y, Qu C, Schallert T, et al.
Therapeutic effects of erythropoietin on histological and functional
outcomes following traumatic brain injury in rats are independent of
hematocrit. Brain Res 2009;1294:153-64.
40. Mogensen J, Miskowiak K, Sørensen TA, Lind CT, Olsen NV,
Springborg JB, et al. Erythropoietin improves place learning in fimbriafornix-transected
and modifies the
normal rats.

Biochem Behav 2004;77(2):381-90.
41. Ozturk E, Demirbilek S, Kadir But A, Saricicek V, Gulec M, Akyol O,
et al. Antioxidant properties of propofol and erythropoietin after closed
head injury in rats. Prog Neuropsychopharmacol Biol Psychiatry
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How to Cite
N, K., P. Kn, S. A, A. D, and V. P. “PHOSPHORYLATION OF TAU PROTEIN IN BRAIN REGIONS OF CHRONIC RENAL FAILURE - INDUCED RATS: AMELIORATIVE EFFECT OF ERYTHROPOIETIN”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 9, no. 3, May 2016, pp. 392-7,
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