Vol 79, No 3 (2020)
Original article
Published online: 2019-10-17

open access

Page views 1400
Article views/downloads 693
Get Citation

Connect on Social Media

Connect on Social Media

Altered cannabinoid receptor expression in pancreatic islets in experimental model of uraemia

P. Nowińska1, M. Niezgoda1, N. Domian1, I. Kasacka1
Pubmed: 31625133
Folia Morphol 2020;79(3):469-475.


Background: Uraemia leads to a number of metabolic and hormonal disorders including defective carbohydrate metabolism. Endocannabinoids exert their effect on insulin and glucagon secretion via activation of specific receptors named CB1 and CB2. For this reason and the absence of reports on location and immunoreactivity of CB1, CB2 receptors compared to immunoreactivity of insulin- and glucagon-secreting cells in experimental uraemia, the author decided to investigate this issue. The aim of the present study was the immunohistochemical localisation and evaluation of cannabinoid receptors (CB1, CB2), insulin and glucagon in the pancreatic islets of uraemic rats.

Materials and methods: Fragments of the rat’s pancreas were collected 28 days after surgical resection of one kidney and removal of 70% of the other kidney cortex. Paraffin-embedded sections were stained with haematoxylin-eosin and immunohistochemical reactions were performed with the use of a specific antibody against CB1-, CB2-receptors, insulin and glucagon.

Results: It was revealed the decreased immunoreactivity of the CB1 receptor and higher intensity of the immunohistochemical reaction against CB2 receptor as compared to the value in the control animals. Significantly higher immunoreactivity of glucagon-positive cells and weaker immunoreactivity of insulin-positive cells were observed in pancreatic islets of uraemic rats.

Conclusions: The obtained results indicate the involvement of cannabinoid receptors in the pathomechanism of carbohydrate metabolism disorders, associated with abnormal secretion of hormones by the α and β cells in uraemia.

Article available in PDF format

View PDF Download PDF file


  1. Anderson RL, Randall MD, Chan SLF. The complex effects of cannabinoids on insulin secretion from rat isolated islets of Langerhans. Eur J Pharmacol. 2013; 706(1-3): 56–62.
  2. Araki T, Ueda M, Ogawa K, et al. Histological pancreatitis in end-stage renal disease. Int J Pancreatol. 1992; 12(3): 263–269.
  3. Baggenstoss AH. The pancreas in uremia; a histopathologic study. Am J Pathol. 1948; 24(5): 1003–1017.
  4. Bátkai S, Osei-Hyiaman D, Pan H, et al. Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. FASEB J. 2007; 21(8): 1788–1800.
  5. Bermúdez-Siva FJ, Serrano A, Diaz-Molina FJ, et al. Activation of cannabinoid CB1 receptors induces glucose intolerance in rats. Eur J Pharmacol. 2006; 531(1-3): 282–284.
  6. Bermudez-Silva FJ, Sanchez-Vera I, Suárez J, et al. Role of cannabinoid CB2 receptors in glucose homeostasis in rats. Eur J Pharmacol. 2007; 565(1-3): 207–211.
  7. Bermúdez-Silva FJ, Suárez J, Baixeras E, et al. Presence of functional cannabinoid receptors in human endocrine pancreas. Diabetologia. 2008; 51(3): 476–487.
  8. Bilbrey GL, Faloona GR, White MG, et al. Hyperglucagonemia of renal failure. J Clin Invest. 1974; 53(3): 841–847.
  9. DeFronzo RA, Andres R, Edgar P, et al. Carbohydrate metabolism in uremia: a review. Medicine (Baltimore). 1973; 52(5): 469–481.
  10. Després JP, Golay A, Sjöström L, et al. Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005; 353(20): 2121–2134.
  11. Duvivier VF, Delafoy-Plasse L, Delion V, et al. Beneficial effect of a chronic treatment with rimonabant on pancreatic function and beta-cell morphology in Zucker Fatty rats. Eur J Pharmacol. 2009; 616(1-3): 314–320.
  12. Emmanouel DS, Lindheimer MD, Katz AI. Pathogenesis of endocrine abnormalities in uremia. Endocr Rev. 1980; 1(1): 28–44.
  13. Getty-Kaushik L, Richard AMT, Deeney JT, et al. The CB1 antagonist rimonabant decreases insulin hypersecretion in rat pancreatic islets. Obesity (Silver Spring). 2009; 17(10): 1856–1860.
  14. González-Mariscal I, Egan JM. Endocannabinoids in the Islets of Langerhans: the ugly, the bad, and the good facts. Am J Physiol Endocrinol Metab. 2018; 315(2): E174–E179.
  15. Hager SR. Insulin resistance of uremia. Am J Kidney Dis. 1989; 14(4): 272–276.
  16. Herman GE, Elfont EA. The taming of immunohistochemistry: the new era of quality control. Biotech Histochem. 1991; 66(4): 194–199.
  17. Janiak P, Poirier B, Bidouard JP, et al. Blockade of cannabinoid CB1 receptors improves renal function, metabolic profile, and increased survival of obese Zucker rats. Kidney Int. 2007; 72(11): 1345–1357.
  18. Juan-Picó P, Fuentes E, Bermúdez-Silva FJ, et al. Cannabinoid receptors regulate Ca(2+) signals and insulin secretion in pancreatic beta-cell. Cell Calcium. 2006; 39(2): 155–162.
  19. Kim W, Lao Q, Shin YK, et al. Cannabinoids induce pancreatic β-cell death by directly inhibiting insulin receptor activation. Sci Signal. 2012; 5(216): ra23.
  20. Koppe L, Nyam E, Vivot K, et al. Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease. J Clin Invest. 2016; 126(9): 3598–3612.
  21. Koppe L, Pelletier CC, Alix PM, et al. Insulin resistance in chronic kidney disease: new lessons from experimental models. Nephrol Dial Transplant. 2014; 29(9): 1666–1674.
  22. Laychock SG, Hoffman JM, Meisel E, et al. Pancreatic islet arachidonic acid turnover and metabolism and insulin release in response to delta-9-tetrahydrocannabinol. Biochem Pharmacol. 1986; 35(12): 2003–2008.
  23. Li C, Jones PM, Persaud SJ. Role of the endocannabinoid system in food intake, energy homeostasis and regulation of the endocrine pancreas. Pharmacol Ther. 2011; 129(3): 307–320.
  24. Lin CY, Hsu YJ, Hsu SC, et al. CB1 cannabinoid receptor antagonist attenuates left ventricular hypertrophy and Akt-mediated cardiac fibrosis in experimental uremia. J Mol Cell Cardiol. 2015; 85: 249–261.
  25. Malenczyk K, Keimpema E, Piscitelli F, et al. Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture. Proc Natl Acad Sci U S A. 2015; 112(45): E6185–E6194.
  26. Matias I, Gonthier MP, Orlando P, et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab. 2006; 91(8): 3171–3180.
  27. Montecucco F, Lenglet S, Braunersreuther V, et al. CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. J Mol Cell Cardiol. 2009; 46(5): 612–620.
  28. Nakata M, Yada T. Cannabinoids inhibit insulin secretion and cytosolic Ca2+ oscillation in islet beta-cells via CB1 receptors. Regul Pept. 2008; 145(1-3): 49–53.
  29. Neirynck N, Vanholder R, Schepers E, et al. An update on uremic toxins. Int Urol Nephrol. 2013; 45(1): 139–150.
  30. Polak A, Harasim E, Chabowski A. Effects of activation of endocannabinoid system on myocardial metabolism. Postepy Hig Med Dosw (Online). 2016; 70(0): 542–555.
  31. Sherwin RS, Bastl C, Finkelstein FO, et al. Influence of uremia and hemodialysis on the turnover and metabolic effects of glucagon. J Clin Invest. 1976; 57(3): 722–731.
  32. Silvestri C, Di Marzo V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab. 2013; 17(4): 475–490.
  33. Vanholder R, De Smet R, Glorieux G, et al. Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int. 2003; 63(5): 1934–1943.
  34. Vilches-Flores A, Delgado-Buenrostro NL, Navarrete-Vázquez G, et al. CB1 cannabinoid receptor expression is regulated by glucose and feeding in rat pancreatic islets. Regul Pept. 2010; 163(1-3): 81–87.
  35. Wang PF, Jiang LS, Bu J, et al. Cannabinoid-2 receptor activation protects against infarct and ischemia-reperfusion heart injury. J Cardiovasc Pharmacol. 2012; 59(4): 301–307.
  36. Xu H, Carrero JJ. Insulin resistance in chronic kidney disease. Nephrology (Carlton). 2017; 22 Suppl 4: 31–34.