Advances in Clinical and Experimental Medicine

Adv Clin Exp Med
Impact Factor (IF) – 1.227
Index Copernicus (ICV 2018) – 157.72
MNiSW – 40
Average rejection rate – 84.38%
ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download PDF

Advances in Clinical and Experimental Medicine

2019, vol. 28, nr 9, September, p. 1161–1170

doi: 10.17219/acem/100647

Publication type: original article

Language: English

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Creative Commons BY-NC-ND 3.0 Open Access

Renal response to tunicamycin-induced endoplasmic reticulum stress in BDNF heterozygous mice

Selma Cırrık1,A,B,C,D,E,F, Gulay Hacioglu2,A,B,C,D,E, Sema Nur Ayyıldız3,B,C,D, Berna Tezcan4,B,C,D, İsmail Abidin5,B,C,D,E, Selcen Aydın-Abidin5,B,C,D,E, Tevfik Noyan3,B,C

1 Faculty of Medicine, Department of Physiology, Ordu University, Turkey

2 Faculty of Medicine, Department of Physiology, Giresun University, Turkey

3 Faculty of Medicine, Department of Medical Biochemistry, Ordu University, Turkey

4 Faculty of Medicine, Department of Histology and Embryology, Giresun University, Turkey

5 Faculty of Medicine, Department of Biophysics, Karadeniz Technical University, Trabzon, Turkey

Abstract

Background. The protective effects of brain-derived neurotrophic factor (BDNF) against endoplasmic reticulum (ER) stress in neuronal tissue and endometrial cells have been reported.
Objectives. The aim of this study was to determine whether endogenously produced BDNF protects the kidneys against tunicamycin-induced (Tm) ER stress.
Material and Methods. Brain-derived neurotrophic factor heterozygous knockout mice (BDNF(+/–)) and their wild-type (WT) littermates were used. The animals were divided into 4 groups: WT, BDNF(+/–), WT+Tm, and BDNF(+/–)+Tm (n = 7 in each group). After 3 days of saline or Tm injection (0.5 mg/kg; intraperitoneally (i.p.)), renal BDNF, glucose-regulated protein 78 (GRP78), and caspase-12 levels as well as serum BDNF concentration were measured with enzyme-linked immunosorbent assay (ELISA). In the kidney sections, hematoxylin & eosin (H&E) staining, GADD153 immunostaining and TUNEL staining were performed. Serum creatinine levels were measured as an indicator of renal function.
Results. Circulating and tissue BDNF levels were significantly lower in the BDNF(+/–) and BDNF(+/–)+Tm groups. Renal levels of GRP78 and caspase-12, apoptotic index, and GADD153 staining were significantly higher in the WT+Tm and BDNF(+/–)+Tm groups. However, apoptosis was more pronounced in the BDNF(+/–)+Tm group than in the WT+Tm group (p < 0.01). Similarly, GADD153 staining was more pronounced in the BDNF(+/–)+Tm group than in the WT+Tm group (p < 0.05). Tm caused a mild deterioration in the kidney tissue of the WT+Tm group, while general deterioration, pyknotic nuclei and swollen cells were observed in the BDNF(+/–)+Tm group. Serum creatinine concentrations were significantly higher in the WT+Tm (p < 0.05) and BDNF(+/–)+Tm (p < 0.05) groups.
Conclusion. This study showed that endogenous BDNF may play a protective role in kidneys against ER stress-induced apoptosis via the suppression of GADD153. As a result, BDNF and related signaling pathways could be considered for therapeutic/protective approaches in kidney disorders.

Key words

apoptosis, endoplasmic reticulum stress, kidney, BDNF heterozygous mice, GADD153

References (41)

  1. Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: Cell life and death decisions. J Clin Invest. 2005;115:2656–2664.
  2. Zhang K, Kaufman RJ. The unfolded protein response: A stress signaling pathway critical for health and disease. Neurology. 2006;66:S102–S109.
  3. Cao SS, Kaufman RJ. Unfolded protein response. Curr Biol. 2012;22(16):R622–626.
  4. Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC. Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene. 2003;22(53):8608–8618.
  5. Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2004;11:381–389.
  6. Yoshida H. ER stress and diseases. FEBS J. 2007;274:630–658.
  7. Vidal RL, Hetz C. Crosstalk between the UPR and autophagy pathway contributes to handling cellular stress in neurodegenerative disease. Autophagy. 2012;8(6):970–972.
  8. Ogawa S, Kitao Y, Hori O. Ischemia-induced neuronal cell death and stress response. Antioxid Redox Signal. 2007;9:573–587.
  9. Cunard R. Endoplasmic reticulum stress in the diabetic kidney: The good, the bad and the ugly. J Clin Med. 2015;4(4):715–740.
  10. Binder DK, Scharfman HE. Brain-derived neurotrophic factor. Growth Factors. 2004;22(3):123–131.
  11. Shibayama E, Koizumi H. Cellular localization of the Trk neurotrophin receptor family in human non-neuronal tissues. Am J Pathol. 1996;148(6):1807–1818.
  12. Yamamoto M, Sobue G, Yamamoto K, Terao S, Mitsuma T. Expression of mRNAs for neurotrophic factors (NGF, BDNF, NT-3, and GDNF) and their receptors (p75NGFR, trkA, trkB, and trkC) in the adult human peripheral nervous system and nonneural tissues. Neurochem Res. 1996;21(8):929–938.
  13. Lommatzsch M, Braun A, Mannsfeldt A, et al. Abundant production of brain-derived neurotrophic factor by adult visceral epithelia. Am J Pathol. 1999;155(4):1183–1193.
  14. Krabbe KS, Nielsen AR, Krogh-Madsen R, et al. Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia. 2007;50(2):431–438.
  15. Manni L, Nikolova V, Vyagova D, Chaldakov GN, Aloe L. Reduced plasma levels of NGF and BDNF in patients with acute coronary syndromes. Int J Cardiol. 2005;102(1):169–171.
  16. Polyakova M, Stuke K, Schuemberg K, Mueller K, Schoenknecht P, Schroeter ML. BDNF as a biomarker for successful treatment of mood disorders: A systematic & quantitative meta-analysis. J Affect Disord. 2015;174:432–440.
  17. Kurajoh M, Kadoya M, Morimoto A, et al. Plasma brain-derived neurotrophic factor concentration is a predictor of chronic kidney disease in patients with cardiovascular risk factors – Hyogo Sleep Cardio-Autonomic Atherosclerosis study. PLoS One. 2017;12(6):e0178686.
  18. Chen G, Fan Z, Wang X, et al. Brain-derived neurotrophic factor suppresses tunicamycin-induced upregulation of CHOP in neurons. J Neurosci Res. 2007;85(8):1674–1684.
  19. Shimoke K, Utsumi T, Kishi S, et al. Prevention of endoplasmic reticulum stress-induced cell death by brain-derived neurotrophic factor in cultured cerebral cortical neurons. Brain Res. 2004;1028(1):105–111.
  20. Lim W, Bae H, Bazer FW, Song G. Brain-derived neurotrophic factor improves proliferation of endometrial epithelial cells by inhibition of endoplasmic reticulum stress during early pregnancy. J Cell Physiol. 2017. doi:10.1002/jcp.25834
  21. Li M, Armelloni S, Zennaro C, et al. BDNF repairs podocyte damage by microRNA-mediated increase of actin polymerization. J Pathol. 2015;235(5):731–744.
  22. García-Suárez O, González-Martínez T, Germana A, et al. Expression of TrkB in the murine kidney. Microsc Res Tech. 2006;69(12):1014–1020.
  23. Inagi R. Endoplasmic reticulum stress in the kidney as a novel mediator of kidney injury. Nephron Exp Nephrol. 2009;112(1):e1–9.
  24. Maekawa H, Inagi R. Stress signal network between hypoxia and ER stress in chronic kidney disease. Front Physiol. 2017;8:74.
  25. Cybulsky AV, Takano T, Papillon J, Bijian K. Role of the endoplasmic reticulum unfolded protein response in glomerular epithelial cell injury. J Biol Chem. 2005;280:24396–24403.
  26. Lindenmeyer MT, Rastaldi MP, Ikehata M, et al. Proteinuria and hyperglycemia induce endoplasmic reticulum stress. J Am Soc Nephrol. 2008;19:2225–2236.
  27. Ohse T, Inagi R, Tanaka T, et al. Albumin induces endoplasmic reticulum stress and apoptosis in renal proximal tubular cells. Kidney Int. 2006;70:1447–1455.
  28. Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci U S A. 1995;92(19):8856–8860.
  29. Abidin I, Yildirim M, Aydin-Abidin S, et al. Penicillin-induced epileptiform activity and EEG spectrum analysis of BDNF heterozygous mice: An in vivo electrophysiological study. Brain Res Bull. 2011;86(3–4):159–164.
  30. De Miguel C, Hamrick WC, Hobbs JL, Pollock DM, Carmines PK, Pollock JS. Endothelin receptor-specific control of endoplasmic reticulum stress and apoptosis in the kidney. Sci Rep. 2017;7:43152.
  31. Hodeify R, Megyesi J, Tarcsafalvi A, et al. Gender differences control the susceptibility to ER stress-induced acute kidney injury. Am J Physiol Renal Physiol. 2013;304(7):F875–882.
  32. Cirrik S, Yavuzer BU, Oner G. Exercise-induced changes in renal URAT1 activity and expression in rats. Ren Fail. 2010;32(7):855–862.
  33. Kernie SG, Liebl DJ, Parada LF. BDNF regulates eating behavior and locomotor activity in mice. EMBO J. 2000;19(6):1290–1300.
  34. Chen FX, Yu YB, Yuan XM, Zuo XL, Li YQ. Brain-derived neurotrophic factor enhances the contraction of intestinal muscle strips induced by SP and CGRP in mice. Regul Pept. 2012;178(1–3):86–94.
  35. Halade GV, Ma Y, Ramirez TA, et al. Reduced BDNF attenuates inflammation and angiogenesis to improve survival and cardiac function following myocardial infarction in mice. Am J Physiol Heart Circ Physiol. 2013;305(12):H1830–1842.
  36. Lyons WE, Mamounas LA, Ricaurte GA, et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci U S A. 1999;96(26):15239–15244.
  37. Duan W, Guo Z, Jiang H, Ware M, Mattson MP. Reversal of behavioral and metabolic abnormalities, and insulin resistance syndrome, by dietary restriction in mice deficient in brain-derived neurotrophic factor. Endocrinology. 2003;144(6):2446–2453.
  38. Samali A, Fitzgerald U, Deegan S, Gupta S. Methods for monitoring endoplasmic reticulum stress and the unfolded protein response. Int J Cell Biol. 2010;2010:830307.
  39. Wei HJ, Xu JH, Li MH, et al. Hydrogen sulfide inhibits homocysteine-induced endoplasmic reticulum stress and neuronal apoptosis in rat hippocampus via upregulation of the BDNF-TrkB pathway. Acta Pharmacol Sin. 2014;35(6):707–715.
  40. Zoladz JA, Śmigielski M, Majerczak J, et al. Hemodialysis decreases serum brain-derived neurotrophic factor concentration in humans. Neurochem Res. 2012;37(12):2715–2724.
  41. Carlisle RE, Brimble E, Werner KE, et al. 4-Phenylbutyrate inhibits tunicamycin-induced acute kidney injury via CHOP/GADD153 repression. PLoS One. 2014;9(1):e84663.