Abstract
To explore the correlations between AMP-activated protein kinase (AMPK) expression and brain inflammatory response and neurological function factors in rats with chronic renal failure. Chronic renal failure models in rats were established, and the healthy control group (normal group) was set. Chronic renal failure model rats were divided into model group (without any treatment), control group (intraperitoneal injection of normal saline), A-769662 group (intraperitoneal injection of AMPK specific activator), and compound C group (intraperitoneal injection of AMPK specific inhibitor). The results of HE staining showed renal tissue enlargement, and significant pathological changes. Compared with the normal group, AMPK level in peripheral blood and AMPK mRNA and protein expressions in brain tissue were significantly reduced, and AMPK pathway activation was significantly inhibited in other groups. Compared with the model group, rats in the A-769662 group had significantly decreased serum creatinine (Scr) and blood urea nitrogen (BUN) levels and γ-aminobutyric acid (γ-GABA) content, significantly increased brain-derived neurotrophic factor (BDNF) positive expressions and 5-hydroxytryptamine (5-HT) content, and decreased interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule 1 (ICAM-1) expressions (all P < 0.05), while it was just the opposite in compound C group (all P < 0.05). There is an apparent correlation between AMPK expression and brain inflammatory response in chronic renal failure rats. AMPK is expected to be an important pathway in the treatment of uremic encephalopathy.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adesso S, Magnus T, Cuzzocrea S, Campolo M, Rissiek B, Paciello O, Autore G, Pinto A, Marzocco S (2017) Indoxyl sulfate affects glial function increasing oxidative stress and neuroinflammation in chronic kidney disease: interaction between astrocytes and microglia. Front Pharmacol 8(370). https://doi.org/10.3389/fphar.2017.00370
Affonso AC, Machado DG, Malgarin F, Fraga DB, Ghedim F, Zugno A, Streck EL, Schuck PF, Ferreira GC (2013) Increased susceptibility of brain acetylcholinesterase activity to methylmalonate in young rats with renal failure. Metab Brain Dis 28:493–500. https://doi.org/10.1007/s11011-013-9396-0
Aghanoori MR, Smith DR, Shariati-Ievari S, Ajisebutu A, Nguyen A, Desmond F, Jesus CHA, Zhou X, Calcutt NA, Aliani M, Fernyhough P (2019) Insulin-like growth factor-1 activates AMPK to augment mitochondrial function and correct neuronal metabolism in sensory neurons in type 1 diabetes. Mol Metab 20:149–165. https://doi.org/10.1016/j.molmet.2018.11.008
Alawdi SH, El-Denshary ES, Safar MM, Eidi H, David MO, Abdel-Wahhab MA (2017) Neuroprotective effect of nanodiamond in Alzheimer’s disease rat model: a pivotal role for modulating NF-κB and STAT3 signaling. Mol Neurobiol 54:1906–1918. https://doi.org/10.1007/s12035-016-9762-0
Balietti M, Giuli C, Conti F (2018) Peripheral blood brain-derived neurotrophic factor as a biomarker of Alzheimer’s disease: are there methodological biases? Mol Neurobiol 55:6661–6672. https://doi.org/10.1007/s12035-017-0866-y
Bearcroft CP, Farthing MJ, Perrett D (1995) Determination of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid and tryptophan in plasma and urine by HPLC with fluorimetric detection. Biomed Chromatogr 9:23–27. https://doi.org/10.1002/bmc.1130090105
Cai HD, Su SL, Qian DW, Guo S, Tao WW, Cong XD, Tang RM, Duan JA (2017) Renal protective effect and action mechanism of Huangkui capsule and its main five flavonoids. J Ethnopharmacol 206:152–159. https://doi.org/10.1016/j.jep.2017.02.046
Cai H, Su S, Li Y, Zeng H, Zhu Z, Guo J, Zhu Y, Guo S, Yu L, Qian D, Tang Y, Duan J (2018) 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 212:153–165. https://doi.org/10.1016/j.jep.2017.09.021
Dai CH, Li J, Chen P, Jiang HG, Wu M, Chen YC (2015) RNA interferences targeting the Fanconi anemia/BRCA pathway upstream genes reverse cisplatin resistance in drug-resistant lung cancer cells. J Biomed Sci 22:77. https://doi.org/10.1186/s12929-015-0185-4
Dominiak A, Wilkaniec A, Jęśko H, Czapski GA, Lenkiewicz AM, Kurek E, Wroczyński P, Adamczyk A (2017) Selol, an organic selenium donor, prevents lipopolysaccharide-induced oxidative stress and inflammatory reaction in the rat brain. Neurochem Int 108:66–77. https://doi.org/10.1016/j.neuint.2017.02.014
Giri S, Nath N, Smith B, Viollet B, Singh AK, Singh I (2004) 5-Aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase. J Neurosci 24:479–487. https://doi.org/10.1523/JNEUROSCI.4288-03.2004
Gong MJ, Han B, Wang SM, Liang SW, Zou ZJ (2016) Icariin reverses corticosterone-induced depression-like behavior, decrease in hippocampal brain-derived neurotrophic factor (BDNF) and metabolic network disturbances revealed by NMR-based metabonomics in rats. J Pharm Biomed Anal 123:63–73. https://doi.org/10.1016/j.jpba.2016.02.001
Hamdi T (2018) Pathogenesis of cerebral edema in patients with acute renal and liver failure and the role of the nephrologist in the management. Curr Opin Nephrol Hypertens 27:289–297. https://doi.org/10.1097/MNH.0000000000000425
Hamed SA (2019) Neurologic conditions and disorders of uremic syndrome of chronic kidney disease: presentations, causes, and treatment strategies. Expert Rev Clin Pharmacol 12:61–90. https://doi.org/10.1080/17512433.2019.1555468
Heidland A, Sebekova K, Klassen A, Palkovits M (2010) Mechanisms of acute uremic encephalopathy: early activation of Fos and Fra-2 gene products in different nuclei/areas of the rat brain. J Ren Nutr 20:S44–S50. https://doi.org/10.1053/j.jrn.2010.05.011
Huang NL, Chiang SH, Hsueh CH, Liang YJ, Chen YJ, Lai LP (2009) Metformin inhibits TNF-α-induced IκB kinase phosphorylation, IκB-α degradation and IL-6 production in endothelial cells through PI3K-dependent AMPK phosphorylation. Int J Cardiol 134:169–175. https://doi.org/10.1016/j.ijcard.2008.04.010
Kalisvaart M, de Haan JE, Hesselink DA, Polak WG, Hansen BE, Jnm I, Gommers D, Metselaar HJ, De JJ (2017) The postreperfusion syndrome is associated with acute kidney injury following donation after brain death liver transplantation. Transpl Int 30:660–669. https://doi.org/10.1111/tri.12891
Kamata K, Uchida M, Takeuchi Y, Takahashi E, Sato N, Miyake Y, Okubo M, Kodama T, Yamaguchi K (1996) Increased serum concentrations of pro-gastrin-releasing peptide in patients with renal dysfunction. Nephrol Dial Transplant 11:1267–1270. https://doi.org/10.1093/ndt/11.7.1267
Kim DM, Lee IH, Song CJ (2016) Uremic encephalopathy: MR imaging findings and clinical correlation. AJNR Am J Neuroradiol 37:1604–1609. https://doi.org/10.3174/ajnr.A4776
Kong L, Liu J, Wang J, Luo Q, Zhang H, Liu B, Xu F, Pang Q, Liu Y, Dong J (2015) Icariin inhibits TNF-α/IFN-γ induced inflammatory response via inhibition of the substance P and p38-MAPK signaling pathway in human keratinocytes. Int Immunopharmacol 29:401–407. https://doi.org/10.1016/j.intimp.2015.10.023
Kuwabara Y, Sasaki M, Hirakata H, Koga H, Nakagawa M, Chen T, Kaneko K, Masuda K, Fujishima M (2002) Cerebral blood flow and vasodilatory capacity in anemia secondary to chronic renal failure. Kidney Int 61:564–569. https://doi.org/10.1046/j.1523-1755.2002.00142.x
Lai YC, Tabima DM, Dube JJ, Hughan KS, Vanderpool RR, Goncharov DA, St Croix CM, Garcia-Ocaña A, Goncharova EA, Tofovic SP (2016) SIRT3-AMP-activated protein kinase activation by nitrite and metformin improves hyperglycemia and normalizes pulmonary hypertension associated with heart failure with preserved ejection fraction. Circulation 133:717–731. https://doi.org/10.1161/CIRCULATIONAHA.115.018935
Lai SW, Chen JH, Lin HY, Liu YS, Tsai CF, Chang PC, Lu DY, Lin C (2018) Regulatory effects of neuroinflammatory responses through brain-derived neurotrophic factor signaling in microglial cells. Mol Neurobiol 55:7487–7499. https://doi.org/10.1007/s12035-018-0933-z
Lu R, Kiernan MC, Murray A, Rosner MH, Ronco C (2015) Kidney-brain crosstalk in the acute and chronic setting. Nat Rev Nephrol 11:707–719. https://doi.org/10.1038/nrneph.2015.131
Lutton EM, Razmpour R, Andrews AM, Cannella LA, Son YJ, Shuvaev VV, Muzykantov VR, Ramirez SH (2017) Acute administration of catalase targeted to ICAM-1 attenuates neuropathology in experimental traumatic brain injury. Sci Rep 7:3846. https://doi.org/10.1038/s41598-017-03309-4
Main BS, Zhang M, Brody KM, Ayton S, Frugier T, Steer D, Finkelstein D, Crack PJ, Taylor JM (2016) Type-1 interferons contribute to the neuroinflammatory response and disease progression of the MPTP mouse model of Parkinson’s disease. Glia 64:1590–1604. https://doi.org/10.1002/glia.23028
Niyazoglu M, Baykara O, Koc A, Aydoğdu P, Onaran I, Dellal FD, Tasan E, Sultuybek GK (2014) Association of PARP-1, NF-κB, NF-κBIA and IL-6, IL-1β and TNF-α with Graves disease and Graves ophthalmopathy. Gene 547:226–232. https://doi.org/10.1016/j.gene.2014.06.038
Palombo F, Masia F, Mattana S, Tamagnini F, Borri P, Langbein W, Fiorettof D (2018) Hyperspectral analysis applied to micro-Brillouin maps of amyloid-beta plaques in Alzheimer’s disease brains. Analyst 143:6095–6102. https://doi.org/10.1039/c8an01291a
Park SY, Jin ML, Chae SY, Ko MJ, Choi YH, Park G, Choi YW (2016) Novel compound from Polygonum multiflorum inhibits inflammatory response in LPS-stimulated microglia by upregulating AMPK/Nrf2 pathways. Neurochem Int 100:21–29. https://doi.org/10.1016/j.neuint.2016.08.006
Reid SNS, Ryu J, Kim Y, Jeon BH (2018) GABA-enriched fermented Laminaria japonica improves cognitive impairment and neuroplasticity in scopolamine- and ethanol-induced dementia model mice. Nutr Res Pract 12:199–207. https://doi.org/10.4162/nrp.2018.12.3.199
Sankar SB, Pybus AF, Liew A, Sanders B, Shah KJ, Wood LB, Buckley EM (2019) Low cerebral blood flow is a non-invasive biomarker of neuroinflammation after repetitive mild traumatic brain injury. Neurobiol Dis 124:544–554. https://doi.org/10.1016/j.nbd.2018.12.018
Sen S, Duman R, Sanacora G (2008) Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry 64:527–532. https://doi.org/10.1016/j.biopsych.2008.05.005
Singh S, Grabner A, Yanucil C, Schramm K, Czaya B, Krick S, Czaja MJ, Bartz R, Abraham R, Marco GSD (2016) Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int 90:985–996. https://doi.org/10.1016/j.kint.2016.05.019
Sundararaman A, Amirtham U, Rangarajan A (2016) Calcium-oxidant signaling network regulates AMP-activated protein kinase (AMPK) activation upon matrix deprivation. J Biol Chem 291:14410–14429. https://doi.org/10.1074/jbc.M116.731257
Tajiri H, Nishi J, Ushijima K, Shimizu T, Ishige T, Shimizu M, Tanaka H, Brooks S (2015) A role for fosfomycin treatment in children for prevention of haemolytic-uraemic syndrome accompanying Shiga toxin-producing Escherichia coli infection. Int J Antimicrob Agents 46:586–589. https://doi.org/10.1016/j.ijantimicag.2015.08.006
Tilstra JS, Avery L, Menk AV, Gordon RA, Smita S, Kane LP, Chikina M, Delgoffe GM, Shlomchik MJ (2018) Kidney-infiltrating T cells in murine lupus nephritis are metabolically and functionally exhausted. J Clin Invest 128:4884–4897. https://doi.org/10.1172/JCI120859
Tsogbadrakh B, Ju KD, Lee J, Han M, Koh J, Yu Y, Lee H, Yu KS, Oh YK, Kim HJ, Ahn C, Oh KH (2018) HL156A, a novel pharmacological agent with potent adenosine-monophosphate-activated protein kinase (AMPK) activator activity ameliorates renal fibrosis in a rat unilateral ureteral obstruction model. PLoS One 13:e0201692. https://doi.org/10.1371/journal.pone.0201692
van Koppen A, Joles JA, Bongartz LG, van den Brandt J, Reichardt HM, Goldschmeding R, Nguyen TQ, Verhaar MC (2012) Healthy bone marrow cells reduce progression of kidney failure better than CKD bone marrow cells in rats with established chronic kidney disease. Cell Transplant 21:2299–2312. https://doi.org/10.3727/096368912X636795
Vehaskari VM (2011) Genetics and CKD. Adv Chronic Kidney Dis 18:317–323. https://doi.org/10.1053/j.ackd.2011.07.001
Wang ZY, Yuan H, Nikolic D, Van Breemen RB, Silverman RB (2006) (+/−)-(1S,2R,5S)-5-Amino-2-fluorocyclohex-3-enecarboxylic acid. A potent GABA aminotransferase inactivator that irreversibly inhibits via an elimination-aromatization pathway. Biochemistry 45:14513–14522. https://doi.org/10.1021/bi061592m
Wang XF, Zhang BH, Lu XQ, Wang P (2018) Beraprost sodium, a stable analogue of PGI2, inhibits the renin-angiotensin system in the renal tissues of rats with chronic renal failure. Kidney Blood Press Res 43:1231–1244. https://doi.org/10.1159/000492405
Xiong DQ, Deng YY, Huang B, Yin CX, Liu B, Shi JS, Gong QH (2016) Icariin attenuates cerebral ischemia–reperfusion injury through inhibition of inflammatory response mediated by NF-κB, PPARα and PPARγ in rats. Int Immunopharmacol 30:157–162. https://doi.org/10.1016/j.intimp.2015.11.035
Yu HY, Cai YB, Liu Z (2015) Activation of AMPK improves lipopolysaccharide-induced dysfunction of the blood-brain barrier in mice. Brain Inj 29:777–784. https://doi.org/10.3109/02699052.2015.1004746
Zhang P, Huang C, Li J, Li T, Guo H, Liu T, Li N, Zhu Q, Guo Y (2016) Globular CTRP9 inhibits oxLDL-induced inflammatory response in RAW 264.7 macrophages via AMPK activation. Mol Cell Biochem 417:67–74. https://doi.org/10.1007/s11010-016-2714-1
Zhang J, Zhang Z, Xiang J, Cai M, Yu Z, Li X, Wu T, Cai D (2017) Neuroprotective effects of echinacoside on regulating the stress-active p38MAPK and NF-κB p52 signals in the mice model of Parkinson’s disease. Neurochem Res 42:975–985. https://doi.org/10.1007/s11064-016-2130-7
Zhang LS, Liu PN, Wen W, Bai XF, Zhang Y, Liu MP, Wang LJ, Wu Y, Yuan ZY, Zhou J (2019) IL-17A contributes to myocardial ischemic injury by activating NLRP3 inflammasome in macrophages through AMPKα/p38MAPK/ERK1/2 signal pathway in mice. Mol Immunol 105:240–250. https://doi.org/10.1016/j.molimm.2018.12.014
Zhou PP, Du SZ, Zhou L, Sun Z, Zhuo LH, He GW, Zhao Y, Wu YL, Zhang XJ (2019) Tetramethylpyrazine-2′O-sodium ferulate provides neuroprotection against neuroinflammation and brain injury in MCAO/R rats by suppressing TLR-4/NF-κB signaling pathway. Pharmacol Biochem Behav 176:33–42. https://doi.org/10.1016/j.pbb.2018.08.010
Funding
This study was supported by the Medical Scientific Research Foundation of Guangdong Province, China (B2015106), and National Natural Science Foundation of China (81470995).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
This study was approved by the Animal Ethic Committee of Nanfang Hospital and complied with the principles of animal management and use.
Conflict of Interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Yang, L., Gong, NR., Zhang, Q. et al. Apparent Correlations Between AMPK Expression and Brain Inflammatory Response and Neurological Function Factors in Rats with Chronic Renal Failure. J Mol Neurosci 68, 204–213 (2019). https://doi.org/10.1007/s12031-019-01299-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-019-01299-8