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Molecular Neurobiology

, Volume 55, Issue 6, pp 5282–5298 | Cite as

Angiotensin Receptor Blockade by Inhibiting Glial Activation Promotes Hippocampal Neurogenesis Via Activation of Wnt/β-Catenin Signaling in Hypertension

  • Shahnawaz Ali Bhat
  • Ruby Goel
  • Shubha Shukla
  • Rakesh Shukla
  • Kashif Hanif
Article

Abstract

Hypertension is one of the major risk factors for central nervous system (CNS) disorders like stroke and Alzheimer’s disease (AD). On the other hand, CNS diseases like AD have been associated with gliosis and impaired neurogenesis. Further, renin angiotensin system (RAS) is intricately associated with hypertension; however, the accumulating evidences suggest that over-activity of RAS may perpetuate the brain inflammation related with AD. Therefore, in the present study, we examined the effect of hypertension and RAS on glial (astrocytes and microglia) activation and hippocampal neurogenesis in a rat model of chronic hypertension. We used Candesartan [angiotensin type 1 receptor (AT1R) blocker (ARB)] both at a low dose (0.1 mg/kg) and anti-hypertensive dose (2 mg/kg) to explore whether their effect on astrocyte and microglial activation, neuroinflammation, and neurogenesis is blood pressure (BP) dependent or independent. Our data revealed that hypertension induces robust microglial and astrocyte activation, neuroinflammation, and cripples hippocampal neurogenesis. Importantly, AT1R blockade by Candesartan, even at low dose (0.1 mg/kg), prevented astrocyte and microglial activation and neuroinflammation in the brain of hypertensive rats. Mechanistically, AT1R blockade prevented the activation of NADPH oxidase, reactive oxygen species (ROS) generation, suppression of MAP kinase and NFкB signaling. Importantly, we, for the first time to our knowledge, provided the evidence that AT1R blockade by activating Wnt/β-catenin signaling, promotes neurogenesis during hypertensive state. We conclude that AT1R blockade prevents astrocyte and microglial activation and improves hippocampal neurogenesis in hypertensive state, independent of BP lowering action.

Keywords

Hypertension Glial activation Neurogenesis AT1R blockade Neuroinflammation 

Notes

Acknowledgments

The authors are highly thankful to Mr. A. L. Vishwakarma, Mrs. M. Chaturvedi and Mr. Dhananjay Sharma for their help with the flow cytometry and confocal microscopy procedures, respectively. We are extremely thankful to Ms. Anika Sood and Ms. Zoya Fatima for quantification of immunohistochemical data in the study. We are highly thankful to Mr. Jitender Singh Kanshana and Mr. Anant Jaiswal for help in real-time PCR studies. We also acknowledge THUNDER (BSC0102) and MoES (GAP0118) for the confocal facility. The CSIR-CDRI Communication number of this article is 9554.

Funding

The study was supported by a financial grant to Kashif Hanif from Department of Biotechnology (DBT, grant No. BT/PR4021/MED/30/676/2011) and CSIR Network Project MIND (BSC0115). Award of research fellowships to SAB from Indian Council of Medical Research (ICMR), and RG from UGC, New Delhi, are greatly acknowledged.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

12035_2017_754_MOESM1_ESM.doc (52.2 mb)
ESM 1 (DOC 53475 kb)

References

  1. 1.
    Stumpf C, John S, Jukic J, Yilmaz A, Raaz D, Schmieder RE, Daniel WG, Garlichs CD (2005) Enhanced levels of platelet P-selectin and circulating cytokines in young patients with mild arterial hypertension. J Hypertens 23:995–1000CrossRefPubMedGoogle Scholar
  2. 2.
    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 59:863–868CrossRefPubMedGoogle Scholar
  3. 3.
    Fogari R, Mugellini A, Zoppi A, Lazzari P, Destro M, Rinaldi A, Preti P (2006) Effect of telmisartan/hydrochlorothiazide vslisinopril/hydrochlorothiazide combination on ambulatory blood pressure and cognitive function in elderly hypertensive patients. J Hum Hypertens 20(3):177–185CrossRefPubMedGoogle Scholar
  4. 4.
    Saavedra JM (2012) Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders. Clin Sci (Lond) 123:567–590CrossRefGoogle Scholar
  5. 5.
    Bhat SA, Goel R, Shukla R, Hanif K (2016) Angiotensin receptor blockade modulates NFкB and STAT3 signalling and inhibits glial activation and neuroinflammation better than angiotensin converting enzyme inhibition. Mol Neurobiol 53(10):6950–6967CrossRefPubMedGoogle Scholar
  6. 6.
    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):1–25CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Guadagno J, Xu X, Karajgikar M, Brown A, Cregan SP (2013) Microglia-derived TNFalpha induces apoptosis in neural precursor cells via transcriptional activation of the Bcl-2 family member puma. Cell Death Dis 4:e538CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Wang L, Hagemann TL, Kalwa H, Michel T, Messing A, Feany MB (2015) Nitric oxide mediates glial-induced neurodegeneration in Alexander disease. Nat Commun 6:8966CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Goel R, Bhat SA, Rajasekar N, Hanif K, Nath C, Shukla R (2015) Hypertension exacerbates predisposition to neurodegeneration and memory impairment in the presence of a neuroinflammatory stimulus: protection by angiotensin converting enzyme inhibition. Pharmacol Biochem Behav 133:132–145CrossRefPubMedGoogle Scholar
  10. 10.
    Stornetta RL, Hawelu-Johnson CL, Guyenet PG, Lynch KR (1988) Astrocytes synthesize angiotensinogen in brain. Science 242:1444–1446CrossRefPubMedGoogle Scholar
  11. 11.
    McKinley MJ, Albiston AL, Allen AM, Mathai ML, May CN, McAllen et al (2003) The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol 35(6):901–918CrossRefPubMedGoogle Scholar
  12. 12.
    Hajjar I, Brown L, Mack WJ, Chui H (2012) Impact of angiotensin receptor blockers on Alzheimer disease neuropathology in a large brain autopsy series. Arch Neurol 69:1632–1638.  https://doi.org/10.1001/archneurol.2012.1010 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kume K, Hanyu H, Sakurai H, Takada Y, Onuma T, Iwamoto T (2012) Effects of telmisartan on cognition and regional cerebral blood flow in hypertensive patients with Alzheimer’s disease. Geriatr Gerontol Int 12:207–214.  https://doi.org/10.1111/j.1447-0594.2011.00746.x CrossRefPubMedGoogle Scholar
  14. 14.
    Mogi M, Li JM, Tsukuda K, Iwanami J, Min LJ, Sakata A, Fujita T, Iwai M et al (2008) Telmisartan prevented cognitive decline partly due to PPAR-gamma activation. Biochem Biophys Res Commun 375(3):446–449CrossRefPubMedGoogle Scholar
  15. 15.
    Tsukuda K, Mogi M, Iwanami J, Min LJ, Sakata A, Jing F, Iwai M, Horiuchi M (2009) Cognitive deficit in amyloid-β-injected mice was improved by pretreatment with a low dose of telmisartan partly because of peroxisome proliferator-activated receptor-γ activation. Hypertension 54:782–787CrossRefPubMedGoogle Scholar
  16. 16.
    Saavedra JM (2016) Evidence to consider angiotensin ii receptor blockers for the treatment of early Alzheimer’s disease. Cell Mol Neurobiol 36(2):259–279.  https://doi.org/10.1007/s10571-015-0327-y CrossRefPubMedGoogle Scholar
  17. 17.
    Danielyan L, Lourhmati A, Verleysdonk S, Kabisch D, Proksch B, Thiess U, Umbreen S, Schmidt B et al (2007) Angiotensin receptor type 1 blockade in astroglia decreases hypoxia-induced cell damage and TNFa release. Neurochem Res 32:1489–1498CrossRefPubMedGoogle Scholar
  18. 18.
    Wu X, Kihara T, Hongo H, Akaike A, Niidome T, Sugimoto H (2010) Angiotensin receptor type 1 antagonists protect against neuronal injury induced by oxygen-glucose depletion. Br J Pharmacol 161:33–50.  https://doi.org/10.1111/j.1476-5381.2010.00840.x CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    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. Psychopharmacology 222(2):185–202CrossRefPubMedGoogle Scholar
  20. 20.
    Tota S, Kamat PK, Awasthi H, Singh N, Raghubir R, Nath C, Hanif K (2009) Candesartan improves memory decline in mice: involvement of AT1 receptors in memory deficit induced by intracerebral streptozotocin. Behav Brain Res 199(2):235–240CrossRefPubMedGoogle Scholar
  21. 21.
    Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140(6):918–934CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Saxe MD, Battaglia F, Wang JW, Malleret G, David DJ, Monckton JE, Garcia et al (2006) Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc Natl Acad Sci U S A 103:17501–17506CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Kempermann G, Song H, Gage FH (2015) Neurogenesis in the adult hippocampus. Cold Spring Harb Perspect Biol 7:a018812CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Pietranera L, Saravia F, Deniselle MCG, Roig P, Lima A, De Nicola AF (2006) Abnormalities of the hippocampus are similar in deoxycorticosterone acetate-salt hypertensive rats and spontaneously hypertensive rats. J Neuroendocrinol 18:466–474CrossRefPubMedGoogle Scholar
  25. 25.
    Pietranera L, Lima A, Roig P, De Nicola AF (2010) Involvement of brain-derived neurotrophic factor and neurogenesis in oestradiol neuroprotection of the hippocampus of hypertensive rats. J Neuroendocrinol 22:1082–1092CrossRefPubMedGoogle Scholar
  26. 26.
    Hwang IK, Yoon YS, Choi JH, Yoo KY, Yi SS, Chung et al (2008) Doublecortin-immunoreactive neuronal precursors in the dentate gyrus of spontaneously hypertensive rats at various age stages: Comparison with Sprague-Dawley rats. J Vet Med Sci 70:373–377CrossRefPubMedGoogle Scholar
  27. 27.
    Perfilieva E, Risedal A, Nyberg J, Johansson BB, Eriksson PS (2001) Gender and strain influence on neurogenesis in dentate gyrus of young rats. J Cereb Blood Flow Metab 21:211–217CrossRefPubMedGoogle Scholar
  28. 28.
    Kronenberg GL, Lippoldt A, Kempermann G (2007) Two genetic rat models of arterial hypertension show different mechanisms by which adult hippocampal neurogenesis is increased. Dev Neurosci 29(1–2):124–133CrossRefPubMedGoogle Scholar
  29. 29.
    Kim S, Zhan Y, Izumi Y, Iwao H (2000) Cardiovascular effects of combination of perindopril, candesartan, and amlodipine in hypertensive rats. Hypertension 35(3):769–774CrossRefPubMedGoogle Scholar
  30. 30.
    Bhat SA, Goel R, Shukla R, Hanif K (2016) Platelet CD40L induces activation of astrocytes and microglia in hypertension. Brain Behav Immun 59:173–189.  https://doi.org/10.1016/j.bbi.2016.09.021 CrossRefPubMedGoogle Scholar
  31. 31.
    Deng W, Aimone JB, Gage FH (2010) New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci 11:339–350CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Mandyam CD, Harburg GC, Eisch AJ (2007) Determination of key aspects of precursor cell proliferation, cell cycle length and kinetics in the adult mouse subgranular zone. Neuroscience 146:108–122CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Paxinos G, Watson C (1982) The rat brain in stereotaxic coordinates. Academic Press, San DiegoGoogle Scholar
  34. 34.
    Nixon K, Crews FT (2004) Temporally specific burst in cell proliferation increases hippocampal neurogenesis in protracted abstinence from alcohol. J Neurosci 24(43):9714–9722CrossRefPubMedGoogle Scholar
  35. 35.
    Morrison HW, Filosa JA (2013) A quantitative spatiotemporal analysis of microglia morphology during ischemic stroke and reperfusion. J Neuroinflammation 10:4CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Khanna V, Jain M, Singh V, Kanshana JS, Prakash P, Barthwal MK et al (2013) Cholesterol diet withdrawal leads to an initial plaque instability and subsequent regression of accelerated iliac artery atherosclerosis in rabbits. PLoS One 8:e77037CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Tiwari SK, Agarwal S, Seth B, Yadav A, Nair S, Bhatnagar P et al (2014) Curcumin-loaded nanoparticles potently induce adult neurogenesis and reverse cognitive deficits in Alzheimer’s disease model via canonical Wnt/beta-catenin pathway. ACS Nano 8:76–103CrossRefPubMedGoogle Scholar
  38. 38.
    Kalani MY, Cheshier SH, Cord BJ, Bababeygy SR, Vogel H, Weissman IL et al (2008) Wnt-mediated self-renewal of neural stem/progenitor cells. Proc Natl Acad Sci U S A 105:16970–16975CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    L’Episcopo F, Tirolo C, Testa N, Caniglia S, Morale MC, Deleidi M et al (2012) Plasticity of subventricular zone neuroprogenitors in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson’s disease involves cross talk between inflammatory and Wnt/beta-catenin signaling pathways: functional consequences for neuroprotection and repair. J Neurosci 32:2062–2085CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Frishman WH (2002) Are antihypertensive agents protective against dementia? A review of clinical and preclinical data. Heart Dis 4:380–386CrossRefPubMedGoogle Scholar
  41. 41.
    Manolio TA, Olson J, Longstreth WT (2003) Hypertension and cognitive function: pathophysiologic effects of hypertension on the brain. Curr Hypertens Rep 5:255–261CrossRefPubMedGoogle Scholar
  42. 42.
    Muldoon LL, Alvarez JI, Begley DJ, Boado RJ, Del Zoppo GJ, Doolittle ND et al (2013) Immunologic privilege in the central nervous system and the blood–brain barrier. J Cereb Blood Flow Metab 33(1):13–21CrossRefPubMedGoogle Scholar
  43. 43.
    Cerbai F, Lana D, Nosi D, Petkova-Kirova P, Zecchi S, Brothers HM et al (2012) The neuronastrocyte- microglia triad in normal brain ageing and in a model of neuroinfl ammation in the rat hippocampus. PLoS One 7(9):e45250CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Jensen CJ, Massie A, De Keyser J (2013) Immune players in the CNS: the astrocyte. J Neuroimmun Pharmacol 8(4):824–839CrossRefGoogle Scholar
  45. 45.
    Patro IK, Pathak S, Patro N (2005) Central responses to peripheral nerve injury: role of non-neuronal cells. Molecular and Cellular Neurobiology 217Google Scholar
  46. 46.
    Patro N, Nagayach A, Patro IK (2010) Iba1 expressing microglia in the dorsal root ganglia become activated following peripheral nerve injury in rats. Indian J Exp Biol 48:110–116PubMedGoogle Scholar
  47. 47.
    Nagayach A, Patro N, Patro I (2014) Astrocytic and microglial response in experimentally induced diabetic rat brain. Metab Brain Dis 29:747–761CrossRefPubMedGoogle Scholar
  48. 48.
    Heneka MT, Wiesinger H, Dumitrescu-Ozimek L, Riederer P, Feinstein DL, Klockgether T (2001) Neuronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease. J Neuropathol Exp Neurol 60(9):906–916CrossRefPubMedGoogle Scholar
  49. 49.
    Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodríguez JJ (2010) Astrocytes in Alzheimer’s disease. Neurotherapeutics 7:399–412CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Shi P, Diez-Freire C, Jun JY, Qi Y (2010) Brain microglial cytokines in neurogenic hypertension. Hypertension 56:297–303CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Sriramula S, Cardinale J, Pariaut R, Francis J (2008) Central nervous system blockade of tumor necrosis factor attenuates angiotensin II induced hypertension. Circulation 118:S383Google Scholar
  52. 52.
    Uttara B, Singh AV, Zamboni P, Mahajan RT (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7(1):65–74CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Kim GH, Kim JE, Rhie SJ, Yoon S (2015) The role of oxidative stress in neurodegenerative diseases. Exp Neurobiol 24(4):325–340CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Li C, Zhao R, Gao K, Wei Z, Yin MY, Lau LT, Chui D, Yu AC (2011) Astrocytes: implications for neuroinflammatory pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 8(1):67–80CrossRefPubMedGoogle Scholar
  55. 55.
    Zhang ZH, Yu Y, Wei SG, Felder RB (2010) Centrally administered lipopolysaccharide elicits sympathetic excitation via NAD(P)H oxidase-dependent mitogen-activated protein kinase signaling. J Hypertens 28(4):806–816CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Pang T, Wang J, Benicky J, Sánchez-Lemus E, Saavedra JM (2012) Telmisartan directly ameliorates the neuronal inflammatory response to IL-1β partly through the JNK/c-Jun and NADPH oxidase pathways. J Neuroinflammation 9:102CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    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(9):2911–2920CrossRefPubMedGoogle Scholar
  58. 58.
    Shi P, Raizada MK, Sumners C (2010) Brain cytokines as neuromodulators in cardiovascular ontrol. Clin Exp Pharmacol Physiol 37(2):e52–e57CrossRefPubMedGoogle Scholar
  59. 59.
    McCarthy CA, Facey LJ, Widdop RE (2014) The protective arms of the renin-angiontensin system in stroke. Curr Hypertens Rep 16(7):440CrossRefPubMedGoogle Scholar
  60. 60.
    Varela-Nallar L, Inestrosa NC (2013) Wnt signaling in the regulation of adult hippocampal neurogenesis. Front Cell Neurosci 7:100.  https://doi.org/10.3389/fncel.2013.00100 CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Gerlach J, Donkels C, Münzner G, Haas CA (2016) Persistent gliosis interferes with neurogenesis in organotypic hippocampal slice cultures. Front Cell Neurosci 10:131CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Belarbi K, Rosi S (2013) Modulation of adult-born neurons in the inflamed hippocampus. Front Cell Neurosci 7:145.  https://doi.org/10.3389/fncel.2013.00145 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Russo I, Barlati S, Bosetti F (2011) Effects of neuroinflammation on the regenerative capacity of brain stem cells. J Neurochem 116:947–956CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Kunke D, Bryja V, Mygland L, Arenas E, Krauss S (2009) Inhibition of canonical Wnt signaling promotes gliogenesis in P0- NSCs. Biochem Biophys Res Commun 386:628–633CrossRefPubMedGoogle Scholar
  65. 65.
    Agrawal A, Shukla R, Tripathi LM, Pandey VC, Srimal RC (1996) Permeability function related to cerebral microvessels enzymes during ageing in rats. Int Jr Devl Neuroscience 14:87–91CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Division of PharmacologyCSIR-Central Drug Research InstituteLucknowIndia
  2. 2.National Institute of Pharmaceutical Education and ResearchRae BareliIndia

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