Skip to main content

Advertisement

SpringerLink
Log in

Angiotensin Receptor Blockade Modulates NFκB and STAT3 Signaling and Inhibits Glial Activation and Neuroinflammation Better than Angiotensin-Converting Enzyme Inhibition

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Neuroinflammation, sustained by astroglial and microglial activation, is the preceding event in neurodegeneration. Various clinical reports showed better neuroprotection by AT1 receptor blockade (ARB) than angiotensin-converting enzyme inhibition (ACEi), but experimental evidences and associated mechanism for this observation are lacking. Therefore, we investigated the effect of ARB, using Candesartan, and ACEi, using Perindopril, in equimolar concentrations in astroglial (C6) and microglial (BV2) cells employing lipopolysaccharide (LPS) to induce neuroinflammation. Further, Candesartan (0.1 mg/kg) and Perindopril (0.1 mg/kg) were orally administered in male SD rats for five consecutive days, and on the fifth day, rats were challenged with LPS (i.p.; 250 μg/kg) and sacrificed after 24 h. LPS-induced neuroinflammation (increased astroglial and microglial activation, IκBα degradation, NFкB nuclear translocation, STAT3 activation, and TNF-α release) was more efficiently prevented by Candesartan (even at lower concentration of 1 nM) than by Perindopril (1 μM) in both the cell types and in rat model of neuroinflammation. In addition, increased AT1 receptor (AT1R) and decreased AT2 receptor (AT2R) expression was observed in LPS-induced neuroinflammation in both in vitro and in vivo studies. Candesartan, as compared to Perindopril, increased the expression of AT2R in both the experimental conditions. Interestingly, concomitant blockade of AT2R by PD123319 significantly reversed the beneficial effects of Candesartan in both the cell types and in rat model of neuroinflammation. Finally, our data emphasize that superiority of Candesartan as compared to Perindopril is due to better activation of AT2R which results in PP2A activation, IκBα stabilization, and suppression of NFкB and STAT3 inflammatory signaling.

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
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Abbreviations

RAS:

Renin angiotensin system

AT1R:

Angiotensin II type 1 receptor

AT2R:

Angiotensin II type 2 receptor

Ang II:

Angiotensin II

ARB:

AT1 receptor blockade

ACEi:

Angiotensin-converting enzyme inhibition

LPS:

Lipopolysaccharide

NFκB:

Nuclear factor-kappa B

pSTAT3:

Phosphorylated signal transducer and activator of transcription 3

GFAP:

Glial fibrillary acidic protein

TNF-α:

Tumor necrosis factor α

IL10:

Interleukin 10

ROS:

Reactive oxygen species

PP2A:

Protein phosphatase-2A

ELISA:

Enzyme-linked immunosorbent assay

BSA:

Bovine serum albumin

DCF-DA:

Dichlorofluorescein diacetate

References

  1. Nickenig G (2004) Should angiotensin II receptor blockers and statins be combined? Circulation 110:1013–1020

    Article  PubMed  Google Scholar 

  2. Schrader J, Luders S, Kulschewski A, Berger J, Zidek W, Treib J, Einhaupl K, Diener HC et al (2003) The ACCESS study: evaluation of acute Candesartan cilexetil therapy in stroke survivors. Stroke 34:1699–1703

    Article  PubMed  Google Scholar 

  3. Kjeldsen SE, Dahlof B, Devereux RB, Julius S, Aurup P, Edelman J, Beevers G, de Faire U et al (2002) Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention for Endpoint reduction (LIFE) substudy. Jama 288:1491–1498

    Article  CAS  PubMed  Google Scholar 

  4. Arima H, Chalmers J (2011) PROGRESS: prevention of recurrent stroke. J Clin Hypertens (Greenwich) 13:693–702

    Article  CAS  Google Scholar 

  5. Saavedra JM (2012) Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders. Clin Sci (Lond) 123:567–590

    Article  CAS  Google Scholar 

  6. Fournier A, Oprisiu-Fournier R, Serot JM, Godefroy O, Achard JM, Faure S, Mazouz H, Temmar M et al (2009) Prevention of dementia by antihypertensive drugs: how AT1-receptor-blockers and dihydropyridines better prevent dementia in hypertensive patients than thiazides and ACE-inhibitors. Expert Rev Neurother 9:1413–1431

    Article  CAS  PubMed  Google Scholar 

  7. Fogari R, Mugellini A, Zoppi A, Marasi G, Pasotti C, Poletti L, Rinaldi A, Preti P (2004) Effects of valsartan compared with enalapril on blood pressure and cognitive function in elderly patients with essential hypertension. Eur J Clin Pharmacol 59:863–868

    Article  CAS  PubMed  Google Scholar 

  8. Li NC, Lee A, Whitmer RA, Kivipelto M, Lawler E, Kazis LE, Wolozin B (2010) Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ 340:b5465

    Article  PubMed  PubMed Central  Google Scholar 

  9. Davies NM, Kehoe PG, Ben-Shlomo Y, Martin RM (2011) Associations of anti- hypertensive treatments with Alzheimer’s disease, vascular dementia, and other dementias. J Alzheimer’s Dis 26:699–708

    Google Scholar 

  10. Saavedra JM (1999) Emerging features of brain angiotensin receptors. Regul Pept 85:31–45

    Article  CAS  PubMed  Google Scholar 

  11. Fuchtbauer L, Groth-Rasmussen M, Holm TH, Lobner M, Toft-Hansen H, Khorooshi R, Owens T (2011) Angiotensin II Type 1 receptor (AT1) signaling in astrocytes regulates synaptic degeneration-induced leukocyte entry to the central nervous system. Brain Behav Immun 25:897–904

    Article  CAS  PubMed  Google Scholar 

  12. Garrido-Gil P, Rodriguez-Pallares J, Dominguez-Meijide A, Guerra MJ, Labandeira-Garcia JL (2013) Brain angiotensin regulates iron homeostasis in dopaminergic neurons and microglial cells. Exp Neurol 250:384–396

    Article  CAS  PubMed  Google Scholar 

  13. Garrido-Gil P, Valenzuela R, Villar-Cheda B, Lanciego JL, Labandeira-Garcia JL (2013) Expression of angiotensinogen and receptors for angiotensin and prorenin in the monkey and human substantia nigra: an intracellular renin-angiotensin system in the nigra. Brain Struct Funct 218:373–388

    Article  CAS  PubMed  Google Scholar 

  14. Shi P, Diez-Freire C, Jun JY, Qi Y, Katovich MJ, Li Q, Sriramula S, Francis J et al (2010) Brain microglial cytokines in neurogenic hypertension. Hypertension 56:297–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T (2000) International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 52:415–472

    PubMed  Google Scholar 

  16. Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T, Ishii K, Yamane J, Yoshimura A et al (2006) Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med 12:829–834

    Article  CAS  PubMed  Google Scholar 

  17. Kang CH, Choi YH, Moon SK, Kim WJ, Kim GY (2013) Quercetin inhibits lipopolysaccharide-induced nitric oxide production in BV2 microglial cells by suppressing the NF-kappaB pathway and activating the Nrf2-dependent HO-1 pathway. Int Immunopharmacol 17:808–813

    Article  CAS  PubMed  Google Scholar 

  18. Tansey MG, McCoy MK, Frank-Cannon TC (2007) Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol 208:1–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Costantino L, Barlocco D (2008) STAT 3 as a target for cancer drug discovery. Curr Med Chem 15:834–843

    Article  CAS  PubMed  Google Scholar 

  20. Abadir PM, Walston JD, Carey RM, Siragy HM (2011) Angiotensin II Type-2 receptors modulate inflammation through signal transducer and activator of transcription proteins 3 phosphorylation and TNFalpha production. J Interferon Cytokine Res 31:471–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Guimond MO, Gallo-Payet N (2012) The angiotensin II type 2 receptor in brain functions: an update. Int J Hypertens 2012:351758

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bononi A, Agnoletto C, De Marchi E, Marchi S, Patergnani S, Bonora M, Giorgi C, Missiroli S et al (2011) Protein kinases and phosphatases in the control of cell fate. Enzyme Res 2011:329098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li J, Culman J, Hortnagl H, Zhao Y, Gerova N, Timm M, Blume A, Zimmermann M et al (2005) Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury. Faseb J 19:617–619

    CAS  PubMed  Google Scholar 

  24. Siragy HM (2009) The potential role of the angiotensin subtype 2 receptor in cardiovascular protection. Curr Hypertens Rep 11:260–262

    Article  CAS  PubMed  Google Scholar 

  25. Dong YF, Kataoka K, Tokutomi Y, Nako H, Nakamura T, Toyama K, Sueta D, Koibuchi N et al (2011) Perindopril, a centrally active angiotensin-converting enzyme inhibitor, prevents cognitive impairment in mouse models of Alzheimer’s disease. Faseb J 25:2911–2920

    Article  CAS  PubMed  Google Scholar 

  26. Tota S, Kamat PK, Saxena G, Hanif K, Najmi AK, Nath C (2012) Central angiotensin converting enzyme facilitates memory impairment in intracerebroventricular streptozotocin treated rats. Behav Brain Res 226:317–330

    Article  CAS  PubMed  Google Scholar 

  27. Tota S, Hanif K, Kamat PK, Najmi AK, Nath C (2012) Role of central angiotensin receptors in scopolamine-induced impairment in memory, cerebral blood flow, and cholinergic function. Psychopharmacol (Berl) 222:185–202

    Article  CAS  Google Scholar 

  28. Niranjan R, Kamat PK, Nath C, Shukla R (2010) Evaluation of guggulipid and nimesulide on production of inflammatory mediators and GFAP expression in LPS stimulated rat astrocytoma, cell line (C6). J Ethnopharmacol 127:625–630

    Article  CAS  PubMed  Google Scholar 

  29. Niranjan R, Nath C, Shukla R (2011) Guggulipid and nimesulide differentially regulated inflammatory genes mRNA expressions via inhibition of NF-kB and CHOP activation in LPS-stimulated rat astrocytoma cells, C6. Cell Mol Neurobiol 31:755–764

    Article  CAS  PubMed  Google Scholar 

  30. Nimmervoll B, White R, Yang JW, An S, Henn C, Sun JJ, Luhmann HJ (2013) LPS-induced microglial secretion of TNFalpha increases activity-dependent neuronal apoptosis in the neonatal cerebral cortex. Cereb Cortex 23:1742–1755

    Article  PubMed  Google Scholar 

  31. Dai XJ, Li N, Yu L, Chen ZY, Hua R, Qin X, Zhang YM (2015) Activation of BV2 microglia by lipopolysaccharide triggers an inflammatory reaction in PC12 cell apoptosis through a toll-like receptor 4-dependent pathway. Cell Stress Chaperones 20:321–331

    Article  CAS  PubMed  Google Scholar 

  32. Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB, Oh KW, Hong JT (2008) Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation 5:37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jeong HK, Jou I, Joe EH (2010) Systemic LPS administration induces brain inflammation but not dopaminergic neuronal death in the substantia nigra. Exp Mol Med 42:823–832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Singh R (2011) Jak2-independent activation of Stat3 by intracellular angiotensin II in human Mesangial cells. J Signal Transduct 2011:257862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Harir N, Pecquet C, Kerenyi M, Sonneck K, Kovacic B, Nyga R, Brevet M, Dhennin I et al (2007) Constitutive activation of Stat5 promotes its cytoplasmic localization and association with PI3-kinase in myeloid leukemias. Blood 109:1678–1686

    Article  CAS  PubMed  Google Scholar 

  36. Rana M, Reddy SS, Maurya P, Singh V, Chaturvedi S, Kaur K, Agarwal H, Ahmad H et al (2015) Turmerone enriched standardized Curcuma longa extract alleviates LPS induced inflammation and cytokine production by regulating TLR4–IRAK1–ROS–MAPK–NFκB axis. J Funct Foods 16:152–163

    Article  CAS  Google Scholar 

  37. Maehama T, Taylor GS, Slama JT, Dixon JE (2000) A sensitive assay for phosphoinositide phosphatases. Anal Biochem 279:248–250

    Article  CAS  PubMed  Google Scholar 

  38. Kamat PK, Rai S, Swarnkar S, Shukla R, Ali S, Najmi AK, Nath C (2013) Okadaic acid-induced Tau phosphorylation in rat brain: role of NMDA receptor. Neuroscience 238:97–113

    Article  CAS  PubMed  Google Scholar 

  39. Harder KW, Owen P, Wong LK, Aebersold R, Clark-Lewis I, Jirik FR (1994) Characterization and kinetic analysis of the intracellular domain of human protein tyrosine phosphatase beta (HPTP beta) using synthetic phosphopeptides. Biochem J 298(Pt 2):395–401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. McGeer EG, McGeer PL (2007) The role of anti-inflammatory agents in Parkinson’s disease. CNS Drugs 21:789–797

    Article  CAS  PubMed  Google Scholar 

  41. Kang W, Hebert JM (2011) Signaling pathways in reactive astrocytes, a genetic perspective. Mol Neurobiol 43:147–154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dandona P, Kumar V, Aljada A, Ghanim H, Syed T, Hofmayer D, Mohanty P, Tripathy D et al (2003) Angiotensin II receptor blocker valsartan suppresses reactive oxygen species generation in leukocytes, nuclear factor-kappa B, in mononuclear cells of normal subjects: evidence of an antiinflammatory action. J Clin Endocrinol Metab 88:4496–4501

    Article  CAS  PubMed  Google Scholar 

  43. Schieffer B, Bunte C, Witte J, Hoeper K, Boger RH, Schwedhelm E, Drexler H (2004) Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease. J Am Coll Cardiol 44:362–368

    Article  CAS  PubMed  Google Scholar 

  44. Haack KK, Mitra AK, Zucker IH (2013) NF-kappaB and CREB are required for angiotensin II type 1 receptor upregulation in neurons. PLoS One 8:e78695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Satou R, Gonzalez-Villalobos RA, Miyata K, Ohashi N, Urushihara M, Acres OW, Navar LG, Kobori H (2009) IL-6 augments angiotensinogen in primary cultured renal proximal tubular cells. Mol Cell Endocrinol 311:24–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gupta A, Rhodes GJ, Berg DT, Gerlitz B, Molitoris BA, Grinnell BW (2007) Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2. Am J Physiol Renal Physiol 293:F245–254

    Article  CAS  PubMed  Google Scholar 

  47. Yamaguchi N, Jesmin S, Zaedi S, Shimojo N, Maeda S, Gando S, Koyama A, Miyauchi T (2006) Time-dependent expression of renal vaso-regulatory molecules in LPS-induced endotoxemia in rat. Peptides 27:2258–2270

    Article  CAS  PubMed  Google Scholar 

  48. Agata J, Ura N, Yoshida H, Shinshi Y, Sasaki H, Hyakkoku M, Taniguchi S, Shimamoto K (2006) Olmesartan is an angiotensin II receptor blocker with an inhibitory effect on angiotensin-converting enzyme. Hypertens Res 29:865–874

    Article  CAS  PubMed  Google Scholar 

  49. Namsolleck P, Recarti C, Foulquier S, Steckelings UM, Unger T (2014) AT(2) receptor and tissue injury: therapeutic implications. Curr Hypertens Rep 16:416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Steckelings UM, Larhed M, Hallberg A, Widdop RE, Jones ES, Wallinder C, Namsolleck P, Dahlof B et al (2011) Non-peptide AT2-receptor agonists. Curr Opin Pharmacol 11:187–192

    Article  CAS  PubMed  Google Scholar 

  51. Dhande I, Ali Q, Hussain T (2013) Proximal tubule angiotensin AT2 receptors mediate an anti-inflammatory response via interleukin-10: role in renoprotection in obese rats. Hypertension 61:1218–1226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Barker TA, Massett MP, Korshunov VA, Mohan AM, Kennedy AJ, Berk BC (2006) Angiotensin II type 2 receptor expression after vascular injury: differing effects of angiotensin-converting enzyme inhibition and angiotensin receptor blockade. Hypertension 48:942–949

    Article  CAS  PubMed  Google Scholar 

  53. Shibata K, Makino I, Shibaguchi H, Niwa M, Katsuragi T, Furukawa T (1997) Up-regulation of angiotensin type 2 receptor mRNA by angiotensin II in rat cortical cells. Biochem Biophys Res Commun 239:633–637

    Article  CAS  PubMed  Google Scholar 

  54. McCarthy CA, Vinh A, Miller AA, Hallberg A, Alterman M, Callaway JK, Widdop RE (2014) Direct angiotensin AT2 receptor stimulation using a novel AT2 receptor agonist, compound 21, evokes neuroprotection in conscious hypertensive rats. PLoS One 9:e95762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rompe F, Artuc M, Hallberg A, Alterman M, Stroder K, Thone-Reineke C, Reichenbach A, Schacherl J et al (2010) Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor kappaB. Hypertension 55:924–931

    Article  CAS  PubMed  Google Scholar 

  56. Zhang T, Park KA, Li Y, Byun HS, Jeon J, Lee Y, Hong JH, Kim JM et al (2013) PHF20 regulates NF-kappaB signalling by disrupting recruitment of PP2A to p65. Nat Commun 4:2062

    PubMed  PubMed Central  Google Scholar 

  57. Liang H, Venema VJ, Wang X, Ju H, Venema RC, Marrero MB (1999) Regulation of angiotensin II-induced phosphorylation of STAT3 in vascular smooth muscle cells. J Biol Chem 274:19846–19851

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was funded by the Department of Biotechnology (DBT, grant No. BT/PR4021/MED/30/676/2011) and CSIR Network Project MIND (BSC0115). Further, Senior Research Fellowships (SRFs) to SAB from Indian Council of Medical Research (ICMR) and RG from University Grants Commission (UGC), New Delhi, are greatly acknowledged.

Author information

Authors and Affiliations

  1. Division of Pharmacology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India

    Shahnawaz Ali Bhat, Ruby Goel, Rakesh Shukla & Kashif Hanif

  2. National Institute of Pharmaceutical Education and Research, Rae Bareli, India

    Kashif Hanif

Authors
  1. Shahnawaz Ali Bhat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruby Goel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rakesh Shukla
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kashif Hanif
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kashif Hanif.

Ethics declarations

Conflict of Interest

The authors have no conflict of interest to declare.

Additional information

CSIR-CDRI Communication Number: 9143

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 9188 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bhat, S.A., Goel, R., Shukla, R. et al. Angiotensin Receptor Blockade Modulates NFκB and STAT3 Signaling and Inhibits Glial Activation and Neuroinflammation Better than Angiotensin-Converting Enzyme Inhibition. Mol Neurobiol 53, 6950–6967 (2016). https://doi.org/10.1007/s12035-015-9584-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-015-9584-5

Keywords

Search

Navigation