Skip to main content

Advertisement

SpringerLink
Log in

Uremia-caused changes of ghrelin system in hippocampus may be associated with impaired cognitive function of hippocampus

  • Nephrology - Original Paper
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Purpose

Hippocampus plays an important role in spatial learning and memory. Ghrelin, a brain-gut peptide, participates in the mnestic functions of hippocampus through its receptor growth hormone secretagogue receptor (GHS-R) distributed in hippocampus. This study was to investigate whether there was a correlation between the changes of ghrelin system in hippocampus and the spatial cognitive impairment caused by chronic renal failure (CRF).

Methods

Sprague–Dawley rats (male, 180 ± 10 g, 7–8 weeks old) were randomly classified into CRF group and control group (n = 18 per group). The CRF model was constructed by 5/6 nephrectomy and the controls treated with sham operation. By the 8th week after the surgery, the spatial cognitive function of rats was assessed by Morris water-maze test (MWM), the protein expression of ghrelin and GHS-R in the hippocampus by immunohistochemistry, and the mRNA expression by real-time PCR. Statistical analysis was performed using ANOVA, Student–Newman–Keuls-q test and Pearson correlation analysis, and P < 0.05 was considered significant.

Results

Compared with the controls, the time spent in “platform” quadrant (TSPQ) of rats with CRF was decreased, but the escape latency (EL) was increased significantly in MWM, and meanwhile the protein and mRNA expression of ghrelin and GHS-R in hippocampus was also increased significantly (P < 0.05 or P < 0.01). Correlation analysis suggested that the TSPQ was negatively but the EL was positively correlated with the mRNA expression of ghrelin and GHS-R (P < 0.01).

Conclusion

The CRF-caused changes of ghrelin system in hippocampus might be correlated with the CRF-caused cognitive function impairment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Murray AM, Tupper DE, Knopman DS, Gilbertson DT, Pederson SL, Li S, Smith GE, Hochhalter AK, Collins AJ, Kane RL (2006) Cognitive impairment in hemodialysis patients is common. Neurology 67(2):216–223. doi:10.1212/01.wnl.0000225182.15532.40

    Article  CAS  PubMed  Google Scholar 

  2. Madan P, Kalra OP, Agarwal S, Tandon OP (2007) Cognitive impairment in chronic kidney disease. Nephrol Dial Transpl 22(2):440–444. doi:10.1093/Ndt/Gfl572

    Article  Google Scholar 

  3. Burgess N, Maguire EA, O’Keefe J (2002) The human hippocampus and spatial and episodic memory. Neuron 35(4):625–641. doi:10.1016/S0896-6273(02)00830-9

    Article  CAS  PubMed  Google Scholar 

  4. Fujisaki K, Tsuruya K, Yamato M, Toyonaga J, Noguchi H, Nakano T, Taniguchi M, Tokumoto M, Hirakata H, Kitazono T (2014) Cerebral oxidative stress induces spatial working memory dysfunction in uremic mice: neuroprotective effect of tempol. Nephrol Dial Transplant 29(3):529–538. doi:10.1093/ndt/gft327

    Article  CAS  PubMed  Google Scholar 

  5. Horvath TL, Diano S, Sotonyi P, Heiman M, Tschop M (2001) Minireview: ghrelin and the regulation of energy balance—a hypothalamic perspective. Endocrinology 142(10):4163–4169. doi:10.1210/endo.142.10.8490

    CAS  PubMed  Google Scholar 

  6. Chen CY, Asakawa A, Fujimiya M, Lee SD, Inui A (2009) Ghrelin gene products and the regulation of food intake and gut motility. Pharmacol Rev 61(4):430–481. doi:10.1124/pr.109.001958

    Article  CAS  PubMed  Google Scholar 

  7. Xu JJ, Wang SZ, Lin YT, Cao LL, Wang R, Chi ZF (2009) Ghrelin protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats. Neurosci Lett 453(1):58–61. doi:10.1016/j.neulet.2009.01.067

    Article  CAS  PubMed  Google Scholar 

  8. Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK (2006) Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol 494(3):528–548. doi:10.1002/Cne.20823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Carlini VP, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, de Barioglio SR (2004) Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem Biophys Res Commun 313(3):635–641. doi:10.1016/j.bbrc.2003.11.150

    Article  CAS  PubMed  Google Scholar 

  10. Fu RG, Wang L, Yao GL, Xue RL, Ge H, Ren ST, Ma LQ, Jiang HL, Liu X (2012) Chronic renal failure impacts the expression of ghrelin and its receptor in hypothalamus and hippocampus. Ren Fail 34(8):1027–1032. doi:10.3109/0886022x.2012.708379

    Article  CAS  PubMed  Google Scholar 

  11. Nunez J (2008) Morris water maze experiment. J Vis Exp. doi:10.3791/897

    Google Scholar 

  12. Swanson LW (2004) Brain maps III: structure of the rat brain: an atlas with printed and electronic templates for data, models, and schematics, 3rd rev. edn. Elsevier, Amsterdam

  13. McElroy MW, Korol DL (2005) Intrahippocampal muscimol shifts learning strategy in gonadally intact young adult female rats. Learn Mem 12(2):150–158. doi:10.1101/Lm.86205

    Article  PubMed  PubMed Central  Google Scholar 

  14. Al Banchaabouchi M, D’Hooge R, Marescau B, De Deyn PP (1999) Behavioural deficits during the acute phase of mild renal failure in mice. Metab Brain Dis 14(3):173–187

    Article  CAS  PubMed  Google Scholar 

  15. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402(6762):656–660. doi:10.1038/45230

    Article  CAS  PubMed  Google Scholar 

  16. Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu HY, Pinto S, Colmers WF, Cone RD, Horvath TL (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37(4):649–661. doi:10.1016/S0896-6273(03)00063-1

    Article  CAS  PubMed  Google Scholar 

  17. Braak H, Braak E, Yilmazer D, Bohl J (1996) Functional anatomy of human hippocampal formation and related structures. J Child Neurol 11(4):265–275

    Article  CAS  PubMed  Google Scholar 

  18. Mcclelland JL, Mcnaughton BL, Oreilly RC (1995) Why there are complementary learning-systems in the hippocampus and neocortex—insights from the successes and failures of connectionist models of learning and memory. Psychol Rev 102(3):419–457. doi:10.1037/0033-295x.102.3.419

    Article  CAS  PubMed  Google Scholar 

  19. Lee I, Hunsaker MR, Kesner RP (2005) The role of hippocampal subregions in detecting spatial novelty. Behav Neurosci 119(1):145–153. doi:10.1037/0735-7044.119.1.145

    Article  PubMed  Google Scholar 

  20. Lee I, Kesner RP (2004) Encoding versus retrieval of spatial memory: double dissociation between the dentate gyrus and the perforant path inputs into CA3 in the dorsal hippocampus. Hippocampus 14(1):66–76. doi:10.1002/hipo.10167

    Article  PubMed  Google Scholar 

  21. Carlini VP, Monzon ME, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, de Barioglio SR (2002) Ghrelin increases anxiety-like behavior and memory retention in rats. Biochem Biophys Res Commun 299(5):739–743. doi:10.1016/S0006-291x(02)02740-7

    Article  CAS  PubMed  Google Scholar 

  22. Ferrini F, Salio C, Lossi L, Merighi A (2009) Ghrelin in central neurons. Curr Neuropharmacol 7(1):37–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschop MH, Horvath TL (2006) Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 9(3):381–388. doi:10.1038/Nn1656

    Article  CAS  PubMed  Google Scholar 

  24. Carlini VP, Gaydou RC, Schioth HB, de Barioglio SR (2007) Selective serotonin reuptake inhibitor (fluoxetine) decreases the effects of ghrelin on memory retention and food intake. Regul Pept 140(1–2):65–73. doi:10.1016/j.regpep.2006.11.012

    Article  CAS  PubMed  Google Scholar 

  25. Jiang H, Betancourt L, Smith RG (2006) Ghrelin amplifies dopamine signaling by cross talk involving formation of growth hormone secretagogue receptor/dopamine receptor subtype 1 heterodimers. Mol Endocrinol 20(8):1772–1785. doi:10.1210/Me.2005-0084

    Article  CAS  PubMed  Google Scholar 

  26. Brouns R, De Deyn PP (2004) Neurological complications in renal failure: a review. Clin Neurol Neurosurg 107(1):1–16. doi:10.1016/j.clineuro.2004.07.012

    Article  CAS  PubMed  Google Scholar 

  27. Fujisaki K, Tsuruya K, Yamato M, Toyonaga J, Noguchi H, Nakano T, Taniguchi M, Tokumoto M, Hirakata H, Kitazono T (2014) Cerebral oxidative stress induces spatial working memory dysfunction in uremic mice: neuroprotective effect of tempol. Nephrol Dial Transpl 29(3):529–538. doi:10.1093/ndt/gft327

    Article  CAS  Google Scholar 

  28. Yoshimoto A, Mori K, Sugawara A, Mukoyama M, Yahata K, Suganami T, Takaya K, Hosoda H, Kojima M, Kangawa K, Nakao K (2002) Plasma ghrelin and desacyl ghrelin concentrations in renal failure. J Am Soc Nephrol 13(11):2748–2752. doi:10.1097/01.Asn.0000032420.12455.74

    Article  CAS  PubMed  Google Scholar 

  29. Fu RG, Xue RL, Wang J, Ma LQ, Lv JR, Wang L, Yao GL, Ge H, Chen Z, Duan ZY, Wang YR (2012) Uremic anorexia and ghrelin expression in the amygdala. Neurosci Lett 527(1):50–54. doi:10.1016/j.neulet.2012.08.040

    Article  CAS  PubMed  Google Scholar 

  30. Buhot HC, Martin S, Segu L (2000) Role of serotonin in memory impairment. Ann Med 32(3):210–221

    Article  CAS  PubMed  Google Scholar 

  31. Bannon MJ, Poosch MS, Yue X, Goebel DJ, Cassin B, Kapatos G (1992) Dopamine transporter messenger-RNA content in human substantia-nigra decreases precipitously with age. Proc Natl Acad Sci USA 89(15):7095–7099. doi:10.1073/pnas.89.15.7095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported by Grants from the National Natural Science Foundation of China (No. 81470968, 81400740, 81300581).

Author information

Author notes

    Authors and Affiliations

    1. Department of Nephrology, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004, Shaanxi Province, People’s Republic of China

      Zhian Lv, Jie Gao, Li Wang, Zhao Chen, Xiaoqin Ma, Jiamei Lu, Linting Wei, Rongguo Fu & Liqun Ma

    2. Department of Anesthesia, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004, Shaanxi Province, People’s Republic of China

      Haozheng Yuan, Jianrui Lv & Rongliang Xue

    3. Department of Integrated Chinese Traditional and Western Medicine, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004, Shaanxi Province, People’s Republic of China

      Xili Wu

    4. Medical Laboratory, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004, Shaanxi Province, People’s Republic of China

      Lei Zhang

    Authors
    1. Zhian Lv
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Jie Gao
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Li Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Zhao Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Haozheng Yuan
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Xiaoqin Ma
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Jiamei Lu
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Jianrui Lv
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Xili Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Lei Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Linting Wei
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Rongliang Xue
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Rongguo Fu
      View author publications

      You can also search for this author in PubMed Google Scholar

    14. Liqun Ma
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Rongguo Fu or Liqun Ma.

    Ethics declarations

    Conflict of interest

    No conflict of interest was declared.

    Additional information

    Zhian Lv and Jie Gao contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Lv, Z., Gao, J., Wang, L. et al. Uremia-caused changes of ghrelin system in hippocampus may be associated with impaired cognitive function of hippocampus. Int Urol Nephrol 48, 807–815 (2016). https://doi.org/10.1007/s11255-016-1228-9

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11255-016-1228-9

    Keywords

    Search

    Navigation