Purinergic Signalling

, Volume 14, Issue 4, pp 345–357 | Cite as

Involvement of P2Y12 receptor of stellate ganglion in diabetic cardiovascular autonomic neuropathy

  • Jingjing Guo
  • Xuan Sheng
  • Yu Dan
  • Yurong Xu
  • Yuanruohan Zhang
  • Huihong Ji
  • Jiayue Wang
  • Zixi Xu
  • Hongyu Che
  • Guodong Li
  • Shangdong Liang
  • Guilin LiEmail author
Original Article


Diabetes as a chronic epidemic disease with obvious symptom of hyperglycemia is seriously affecting human health globally due to the diverse diabetic complications. Diabetic cardiovascular autonomic neuropathy (DCAN) is a common complication of both type 1 and type 2 diabetes and incurs high morbidity and mortality. However, the underlying mechanism for DCAN is unclear. It is well known that purinergic signaling is involved in the regulation of cardiovascular function. In this study, we examined whether the P2Y12 receptor could mediate DCAN-induced sympathetic reflexes. Our results revealed that the abnormal changes of blood pressure, heart rate, heart rate variability, and sympathetic nerve discharge were improved in diabetic rats treated with P2Y12 short hairpin RNA (shRNA). Meanwhile, the expression of P2Y12 receptor, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and connexin 43 (Cx43) in stellate ganglia (SG) was decreased in P2Y12 shRNA-treated diabetic rats. In addition, knocking down the P2Y12 receptor also inhibited the activation of p38 MARK in the SG of diabetic rats. Taken together, these findings demonstrated that P2Y12 receptor in the SG may participate in developing diabetic autonomic neuropathy, suggesting that the P2Y12 receptor could be a potential therapeutic target for the treatment of DCAN.


P2Y12 receptor Diabetic cardiovascular autonomic neuropathy Stellate ganglia Satellite glial cells 



This study was supported by grants from the National Natural Science Foundation of China (81560219, 31560276, 81570735, and 81200853), a grant from the young scientist training object of Jiangxi Province (20153BCB23030), and a grant from the Natural Science Foundation of Jiangxi Province (20171BAB205025).

Compliance with ethical standards

Conflicts of interest

Jingjing Guo declares that she has no conflict of interest.

Xuan Sheng declares that she has no conflict of interest.

Yu Dan declares that she has no conflict of interest.

Yurong Xu declares that she has no conflict of interest.

Yuanruohan Zhang declares that he has no conflict of interest.

Huihong Ji declares that she has no conflict of interest.

Jiayue Wang declares that she has no conflict of interest.

Zixi Xu declares that she has no conflict of interest.

Hongyu Che declares that she has no conflict of interest.

Guodong Li declares that he has no conflict of interest.

Shangdong Liang declares that he has no conflict of interest.

Guilin Li declares that she has no conflict of interest.

Ethical approval

The use of animals was reviewed and approved by the Animal Care and Use Committees of Nanchang University Medical Schools.


  1. 1.
    Li XQ, Zheng X, Chen M, Zhao MH (2017) Characteristics of diabetic nephropathy patients without diabetic retinopathy: a retrospective observational study. Medicine (Baltimore) 96:e6805CrossRefGoogle Scholar
  2. 2.
    Ma RC, Chan JC (2013) Type 2 diabetes in East Asians: similarities and differences with populations in Europe and the United States. Ann N Y Acad Sci 1281:64–91CrossRefGoogle Scholar
  3. 3.
    Rahelic D (2016) 7th edition of Idf diabetes atlas—call for immediate action. Lijec Vjesn 138:57–58PubMedGoogle Scholar
  4. 4.
    Jin J, Wang W, Zhu L, Gu T, Niu Q et al (2017) Cardiovascular autonomic neuropathy is an independent risk factor for left ventricular diastolic dysfunction in patients with type 2 diabetes. Biomed Res Int 2017:3270617PubMedPubMedCentralGoogle Scholar
  5. 5.
    Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M et al (2010) Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33:2285–2293CrossRefGoogle Scholar
  6. 6.
    Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, Stevens M, Kempler P, Hilsted J, Tesfaye S, Low P, Valensi P, on behalf of The Toronto Consensus Panel on Diabetic Neuropathy (2011) Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 27:639–653CrossRefGoogle Scholar
  7. 7.
    Pop-Busui R, Low PA, Waberski BH, Martin CL, Albers JW, Feldman EL, Sommer C, Cleary PA, Lachin JM, Herman WH, for the DCCT/EDIC Research Group (2009) Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC). Circulation 119:2886–2893CrossRefGoogle Scholar
  8. 8.
    Burnstock G (2007) Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 87:659–797CrossRefGoogle Scholar
  9. 9.
    Qureshi IA, Mattick JS, Mehler MF (2010) Long non-coding RNAs in nervous system function and disease. Brain Res 1338:20–35CrossRefGoogle Scholar
  10. 10.
    Burnstock G, Krugel U, Abbracchio MP, Illes P (2011) Purinergic signalling: from normal behaviour to pathological brain function. Prog Neurobiol 95:229–274CrossRefGoogle Scholar
  11. 11.
    Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D, Conley PB (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409:202–207CrossRefGoogle Scholar
  12. 12.
    Gachet C (2012) P2Y(12) receptors in platelets and other hematopoietic and non-hematopoietic cells. Purinergic Signal 8:609–619CrossRefGoogle Scholar
  13. 13.
    Sasaki Y, Hoshi M, Akazawa C, Nakamura Y, Tsuzuki H, Inoue K, Kohsaka S (2003) Selective expression of Gi/o-coupled ATP receptor P2Y12 in microglia in rat brain. Glia 44:242–250CrossRefGoogle Scholar
  14. 14.
    Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, Julius D (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9:1512–1519CrossRefGoogle Scholar
  15. 15.
    Suadicani SO, Cherkas PS, Zuckerman J, Smith DN, Spray DC, Hanani M (2010) Bidirectional calcium signaling between satellite glial cells and neurons in cultured mouse trigeminal ganglia. Neuron Glia Biol 6:43–51CrossRefGoogle Scholar
  16. 16.
    Yi Z, Xie L, Zhou C, Yuan H, Ouyang S et al (2017) P2Y12 receptor upregulation in satellite glial cells is involved in neuropathic pain induced by HIV glycoprotein 120 and 2′,3′-dideoxycytidine. Purinergic Signal.
  17. 17.
    Tu G, Li G, Peng H, Hu J, Liu J, Kong F, Liu S, Gao Y, Xu C, Xu X, Qiu S, Fan B, Zhu Q, Yu S, Zheng C, Wu B, Peng L, Song M, Wu Q, Liang S (2013) P2X(7) inhibition in stellate ganglia prevents the increased sympathoexcitatory reflex via sensory-sympathetic coupling induced by myocardial ischemic injury. Brain Res Bull 96:71–85CrossRefGoogle Scholar
  18. 18.
    Burnstock G, Pelleg A (2015) Cardiac purinergic signalling in health and disease. Purinergic Signal 11:1–46CrossRefGoogle Scholar
  19. 19.
    Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, van Giezen JJ, Jonasson J et al (2013) Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. J Am Coll Cardiol 61:723–727CrossRefGoogle Scholar
  20. 20.
    Bell RM, Sivaraman V, Kunuthur SP, Cohen MV, Downey JM, Yellon DM (2015) Cardioprotective properties of the platelet P2Y12 receptor inhibitor, cangrelor: protective in diabetics and reliant upon the presence of blood. Cardiovasc Drugs Ther 29:415–418CrossRefGoogle Scholar
  21. 21.
    Yang XM, Liu Y, Cui L, Yang X, Liu Y, Tandon N, Kambayashi J, Downey JM, Cohen MV (2013) Platelet P2Y12 blockers confer direct postconditioning-like protection in reperfused rabbit hearts. J Cardiovasc Pharmacol Ther 18:251–262CrossRefGoogle Scholar
  22. 22.
    Jia T, Rao J, Zou L, Zhao S, Yi Z et al (2017) Nanoparticle-encapsulated curcumin inhibits diabetic neuropathic pain involving the P2Y12 receptor in the dorsal root ganglia. Front Neurosci 11:755CrossRefGoogle Scholar
  23. 23.
    Zou L, Gong Y, Zhao S, Yi Z, Han X, Wu B, Jia T, Li L, Yuan H, Shi L, Zhang C, Gao Y, Li G, Xu H, Liu H, Liang S, Liu S (2018) Downregulation of P2Y12 in the superior cervical ganglia alleviates abnormal sympathetic activity after myocardial ischemia. J Cell Physiol 233:3375–3383CrossRefGoogle Scholar
  24. 24.
    Tu G, Zou L, Liu S, Wu B, Lv Q, Wang S, Xue Y, Zhang C, Yi Z, Zhang X, Li G, Liang S (2016) Long noncoding NONRATT021972 siRNA normalized abnormal sympathetic activity mediated by the upregulation of P2X7 receptor in superior cervical ganglia after myocardial ischemia. Purinergic Signal 12:521–535CrossRefGoogle Scholar
  25. 25.
    Pather N, Partab P, Singh B, Satyapal KS (2003) The sympathetic contributions to the cardiac plexus. Surg Radiol Anat 25:210–215CrossRefGoogle Scholar
  26. 26.
    Fudim M, Boortz-Marx R, Ganesh A, Waldron NH, Qadri YJ, Patel CB, Milano CA, Sun AY, Mathew JP, Piccini JP (2017) Stellate ganglion blockade for the treatment of refractory ventricular arrhythmias: a systematic review and meta-analysis. J Cardiovasc Electrophysiol 28:1460–1467CrossRefGoogle Scholar
  27. 27.
    Hanani M (2010) Satellite glial cells in sympathetic and parasympathetic ganglia: in search of function. Brain Res Rev 64:304–327CrossRefGoogle Scholar
  28. 28.
    Costa FA, Moreira Neto FL (2015) Satellite glial cells in sensory ganglia: its role in pain. Rev Bras Anestesiol 65:73–81CrossRefGoogle Scholar
  29. 29.
    Kobayashi K, Yamanaka H, Noguchi K (2013) Expression of ATP receptors in the rat dorsal root ganglion and spinal cord. Anat Sci Int 88:10–16CrossRefGoogle Scholar
  30. 30.
    Horvath G, Goloncser F, Csolle C, Kiraly K, Ando RD et al (2014) Central P2Y12 receptor blockade alleviates inflammatory and neuropathic pain and cytokine production in rodents. Neurobiol Dis 70:162–178CrossRefGoogle Scholar
  31. 31.
    Katagiri A, Shinoda M, Honda K, Toyofuku A, Sessle BJ et al (2012) Satellite glial cell P2Y12 receptor in the trigeminal ganglion is involved in lingual neuropathic pain mechanisms in rats. Mol Pain 8:23CrossRefGoogle Scholar
  32. 32.
    Feldman-Goriachnik R, Belzer V, Hanani M (2015) Systemic inflammation activates satellite glial cells in the mouse nodose ganglion and alters their functions. Glia 63:2121–2132. CrossRefPubMedGoogle Scholar
  33. 33.
    Rao S, Liu S, Zou L, Jia T, Zhao S, Wu B, Yi Z, Wang S, Xue Y, Gao Y, Xu C, Li G, Xu H, Zhang C, Liang S (2017) The effect of sinomenine in diabetic neuropathic pain mediated by the P2X3 receptor in dorsal root ganglia. Purinergic Signal 13:227–235CrossRefGoogle Scholar
  34. 34.
    Liu S, Zou L, Xie J, Xie W, Wen S, Xie Q, Gao Y, Li G, Zhang C, Xu C, Xu H, Wu B, Lv Q, Zhang X, Wang S, Xue Y, Liang S (2016) LncRNA NONRATT021972 siRNA regulates neuropathic pain behaviors in type 2 diabetic rats through the P2X7 receptor in dorsal root ganglia. Mol Brain 9:44CrossRefGoogle Scholar
  35. 35.
    Li G, Xu H, Zhu S, Xu W, Qin S, Liu S, Tu G, Peng H, Qiu S, Yu S, Zhu Q, Fan B, Zheng C, Li G, Liang S (2013) Effects of neferine on CCL5 and CCR5 expression in SCG of type 2 diabetic rats. Brain Res Bull 90:79–87CrossRefGoogle Scholar
  36. 36.
    Wang M, Li S, Zhou X, Huang B, Zhou L, Li X, Meng G, Yuan S, Wang Y, Wang Z, Wang S, Yu L, Jiang H (2017) Increased inflammation promotes ventricular arrhythmia through aggravating left stellate ganglion remodeling in a canine ischemia model. Int J Cardiol 248:286–293CrossRefGoogle Scholar
  37. 37.
    Lu Y, Wu Q, Liu LZ, Yu XJ, Liu JJ et al (2018) Pyridostigmine protects against cardiomyopathy associated with adipose tissue browning and improvement of vagal activity in high-fat diet rats. Biochim Biophys Acta 1864:1037–1050CrossRefGoogle Scholar
  38. 38.
    Kenney MJ, Ganta CK, Fels RJ (2013) Disinhibition of RVLM neural circuits and regulation of sympathetic nerve discharge at peak hyperthermia. J Appl Physiol (1985) 115:1297–1303CrossRefGoogle Scholar
  39. 39.
    Tiftikcioglu BI, Bilgin S, Duksal T, Kose S, Zorlu Y (2016) Autonomic neuropathy and endothelial dysfunction in patients with impaired glucose tolerance or type 2 diabetes mellitus. Medicine (Baltimore) 95:e3340CrossRefGoogle Scholar
  40. 40.
    Erlinge D, Burnstock G (2008) P2 receptors in cardiovascular regulation and disease. Purinergic Signal 4:1–20CrossRefGoogle Scholar
  41. 41.
    Magni G, Ceruti S (2013) P2Y purinergic receptors: new targets for analgesic and antimigraine drugs. Biochem Pharmacol 85:466–477CrossRefGoogle Scholar
  42. 42.
    Burnstock G, Novak I (2013) Purinergic signalling and diabetes. Purinergic Signal 9:307–324CrossRefGoogle Scholar
  43. 43.
    Wu B, Zhang C, Zou L, Ma Y, Huang K, Lv Q, Zhang X, Wang S, Xue Y, Yi Z, Jia T, Zhao S, Liu S, Xu H, Li G, Liang S (2016) LncRNA uc.48+ siRNA improved diabetic sympathetic neuropathy in type 2 diabetic rats mediated by P2X7 receptor in SCG. Auton Neurosci 197:14–18CrossRefGoogle Scholar
  44. 44.
    Morel O, Kessler L, Ohlmann P, Bareiss P (2010) Diabetes and the platelet: toward new therapeutic paradigms for diabetic atherothrombosis. Atherosclerosis 212:367–376CrossRefGoogle Scholar
  45. 45.
    Tarvainen MP, Laitinen TP, Lipponen JA, Cornforth DJ, Jelinek HF (2014) Cardiac autonomic dysfunction in type 2 diabetes - effect of hyperglycemia and disease duration. Front Endocrinol (Lausanne) 5:130CrossRefGoogle Scholar
  46. 46.
    Jin SX, Zhuang ZY, Woolf CJ, Ji RR (2003) p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci 23:4017–4022CrossRefGoogle Scholar
  47. 47.
    Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ (2002) p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36:57–68CrossRefGoogle Scholar
  48. 48.
    Liu M, Yao M, Wang H, Xu L, Zheng Y, Huang B, Ni H, Xu S, Zhou X, Lian Q (2017) P2Y12 receptor-mediated activation of spinal microglia and p38MAPK pathway contribute to cancer-induced bone pain. J Pain Res 10:417–426CrossRefGoogle Scholar
  49. 49.
    Kobayashi K, Yamanaka H, Fukuoka T, Dai Y, Obata K, Noguchi K (2008) P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain. J Neurosci 28:2892–2902CrossRefGoogle Scholar
  50. 50.
    Tatsumi E, Yamanaka H, Kobayashi K, Yagi H, Sakagami M, Noguchi K (2015) RhoA/ROCK pathway mediates p38 MAPK activation and morphological changes downstream of P2Y12/13 receptors in spinal microglia in neuropathic pain. Glia 63:216–228CrossRefGoogle Scholar
  51. 51.
    Ceruti S, Fumagalli M, Villa G, Verderio C, Abbracchio MP (2008) Purinoceptor-mediated calcium signaling in primary neuron-glia trigeminal cultures. Cell Calcium 43:576–590CrossRefGoogle Scholar
  52. 52.
    Hanani M (2005) Satellite glial cells in sensory ganglia: from form to function. Brain Res Brain Res Rev 48:457–476CrossRefGoogle Scholar
  53. 53.
    Heinzmann S, McMahon SB (2011) New molecules for the treatment of pain. Curr Opin Support Palliat Care 5:111–115CrossRefGoogle Scholar
  54. 54.
    Warwick RA, Hanani M (2013) The contribution of satellite glial cells to chemotherapy-induced neuropathic pain. Eur J Pain 17:571–580CrossRefGoogle Scholar
  55. 55.
    Spray DC, Hanani M (2017) Gap junctions, pannexins and pain. Neurosci Lett.
  56. 56.
    Lurtz MM, Louis CF (2007) Purinergic receptor-mediated regulation of lens connexin43. Invest Ophthalmol Vis Sci 48:4177–4186CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Jingjing Guo
    • 1
  • Xuan Sheng
    • 1
  • Yu Dan
    • 1
  • Yurong Xu
    • 1
  • Yuanruohan Zhang
    • 2
  • Huihong Ji
    • 3
  • Jiayue Wang
    • 3
  • Zixi Xu
    • 3
  • Hongyu Che
    • 2
  • Guodong Li
    • 1
    • 4
  • Shangdong Liang
    • 1
  • Guilin Li
    • 1
    Email author
  1. 1.Department of PhysiologyMedical College of Nanchang UniversityNanchangChina
  2. 2.Queen Mary SchoolMedical College of Nanchang UniversityNanchangChina
  3. 3.Department of the First ClinicalMedical College of Nanchang UniversityNanchangChina
  4. 4.Department of Anatomy, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore

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