Molecular and Cellular Biochemistry

, Volume 462, Issue 1–2, pp 123–132 | Cite as

The protective effect of cannabinoid type 2 receptor activation on renal ischemia–reperfusion injury

  • Murat ÇakırEmail author
  • Suat Tekin
  • Züleyha Doğanyiğit
  • Pınar Çakan
  • Emin Kaymak


Kidney ischemia reperfusion (IR) injury is an important health problem resulting in acute renal failure. After IR, the inflammatory and apoptotic process is triggered. The relation of Cannabinoid type 2 (CB2) receptor with inflammatory and apoptotic process has been determined. The CB2 receptor has been shown to be localized in glomeruli and tubules in human and rat kidney. Activation of CB2 receptor with JWH-133 has been shown to reduce apoptosis and inflammation. In this study, it was investigated whether CB2 activation with selective CB2 receptor agonist JWH-133 was protective against renal IR injury. Male Sprague–Dawley rats were divided into 5 groups (n = 45). Bilateral ischemia was treated to the IR group rat’s kidneys for 45 min and then reperfusion was performed for 24 h. Three different doses of JWH-133 (0.2, 1 and 5 mg/kg) were administered to the treatment groups at the onset of ischemia. The JWH-133 application at three different doses decreased the glomerular and tubular damage. Additionally, in the renal tissue, nuclear factor-κB, tumour necrosis factor alpha, interleukin-1beta, and caspase-3 levels decreased immunohistochemically. Similarly, JWH-133 application decreased the serum tumour necrosis factor alpha, blood urea nitrogen, creatinine, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, Cystatin C, interleukin-18, interleukin-1beta, interleukin-6, and interleukin-10 levels. We found that JWH-133 and CB2 receptor activation had a curative effect against kidney IR damage. JWH-133 may be a new therapeutic agent in preventing kidney IR damage.


Kidney Cannabinoid type 2 receptor Ischemia–reperfusion injury JWH-133 


Author contributions

MÇ projected and conducted the study, analyzed the data, and wrote the study. MÇ and ST operated rats. ZD and EK performed histopathological and immunohistochemical analyzes. PÇ made ELISA analysis.


We were supported by Bozok University, Department of Scientific Research Projects, (Project No: 6602b-TF/18-193).

Compliance with ethical standards

Conflict of interest

Authors declare no conflict of interest.


  1. 1.
    Bucuvic EM, Ponce D, Balbi AL (2011) Risk factors for mortality in acute kidney injury. Rev Assoc Med Bras (1992) 57:158–163CrossRefGoogle Scholar
  2. 2.
    Hsu CY, McCulloch CE, Fan D, Ordonez JD, Chertow GM, Go AS (2007) Community-based incidence of acute renal failure. Kidney Int 72:208–212. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ozer Sehirli A, Sener G, Ercan F (2009) Protective effects of pycnogenol against ischemia reperfusion-induced oxidative renal injury in rats. Ren Fail 31:690–697. CrossRefPubMedGoogle Scholar
  4. 4.
    Eraslan E, Tanyeli A, Polat E (2019) 8-Br-cADPR, a TRPM2 ion channel antagonist, inhibits renal ischemia-reperfusion injury. J Cell Physiol 234:4572–4581. CrossRefPubMedGoogle Scholar
  5. 5.
    Cakir M, Tekin S, Taslidere A, Cakan P, Duzova H, Gul CC (2018) Protective effect of N-(p-amylcinnamoyl) anthranilic acid, phospholipase A2 enzyme inhibitor, and transient receptor potential melastatin-2 channel blocker against renal ischemia-reperfusion injury. J Cell Biochem. CrossRefPubMedGoogle Scholar
  6. 6.
    Lawrence T (2009) The nuclear factor NF-kappa B pathway in inflammation. Cold Spring Harb Persp Biol 1:a001651. CrossRefGoogle Scholar
  7. 7.
    Moynagh PN (2005) The NF-kappaB pathway. J Cell Sci 118:4589–4592. CrossRefPubMedGoogle Scholar
  8. 8.
    Beker BM, Corleto MG, Fieiras C, Musso CG (2018) Novel acute kidney injury biomarkers: their characteristics, utility and concerns. Int Urol Nephrol 50:705–713. CrossRefPubMedGoogle Scholar
  9. 9.
    Kokkoris S, Pipili C, Grapsa E, Kyprianou T, Nanas S (2013) Novel biomarkers of acute kidney injury in the general adult ICU: a review. Ren Fail 35:579–591. CrossRefPubMedGoogle Scholar
  10. 10.
    Teo SH, Endre ZH (2017) Biomarkers in acute kidney injury (AKI). Best Pract Res Clin Anaesthesiol 31:331–344. CrossRefPubMedGoogle Scholar
  11. 11.
    Picone RP, Kendall DA (2015) Minireview: from the bench, toward the clinic: therapeutic opportunities for cannabinoid receptor modulation. Mol Endocrinol 29:801–813. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Barutta F, Piscitelli F, Pinach S, Bruno G, Gambino R, Rastaldi MP, Salvidio G, Di Marzo V, Cavallo Perin P, Gruden G (2011) Protective role of cannabinoid receptor type 2 in a mouse model of diabetic nephropathy. Diabetes 60:2386–2396. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Deutsch DG, Goligorsky MS, Schmid PC, Krebsbach RJ, Schmid HHO, Das SK, Dey SK, Arreaza G, Thorup C, Stefano G, Moore LC (1997) Production and physiological actions of anandamide in the vasculature of the rat kidney. J Clin Investig 100:1538–1546. CrossRefPubMedGoogle Scholar
  14. 14.
    Jenkin KA, McAinch AJ, Briffa JF, Zhang Y, Kelly DJ, Pollock CA, Poronnik P, Hryciw DH (2013) Cannabinoid receptor 2 expression in human proximal tubule cells is regulated by albumin independent of ERK1/2 signaling. Cell Physiol Biochem 32:1309–1319. CrossRefPubMedGoogle Scholar
  15. 15.
    Jenkin KA, McAinch AJ, Grinfeld E, Hryciw DH (2010) Role for cannabinoid receptors in human proximal tubular hypertrophy. Cell Physiol Biochem 26:879–886. CrossRefPubMedGoogle Scholar
  16. 16.
    Moradi H, Oveisi F, Khanifar E, Moreno-Sanz G, Vaziri ND, Piomelli D (2016) Increased renal 2-arachidonoylglycerol level is associated with improved renal function in a mouse model of acute kidney injury. Cannabis Cannabinoid Res 1:218–228. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Pressly JD, Mustafa SM, Adibi AH, Alghamdi S, Pandey P, Roy KK, Doerksen RJ, Moore BM Jr, Park F (2018) Selective cannabinoid 2 receptor stimulation reduces tubular epithelial cell damage after renal ischemia-reperfusion injury. J Pharmacol Exp Ther 364:287–299. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Mukhopadhyay P, Rajesh M, Pan H, Patel V, Mukhopadhyay B, Batkai S, Gao B, Hasko G, Pacher P (2010) Cannabinoid-2 receptor limits inflammation, oxidative/nitrosative stress, and cell death in nephropathy. Free Radic Biol Med 48:457–467. CrossRefPubMedGoogle Scholar
  19. 19.
    Zoja C, Locatelli M, Corna D, Villa S, Rottoli D, Nava V, Verde R, Piscitelli F, Di Marzo V, Fingerle J, Adam JM, Rothenhaeusler B, Ottaviani G, Benardeau A, Abbate M, Remuzzi G, Benigni A (2016) Therapy with a selective cannabinoid receptor type 2 agonist limits albuminuria and renal injury in mice with type 2 diabetic nephropathy. Nephron 132:59–69. CrossRefPubMedGoogle Scholar
  20. 20.
    Jenkin KA, O’Keefe L, Simcocks AC, Briffa JF, Mathai ML, McAinch AJ, Hryciw DH (2016) Renal effects of chronic pharmacological manipulation of CB2 receptors in rats with diet-induced obesity. Br J Pharmacol 173:1128–1142. CrossRefPubMedGoogle Scholar
  21. 21.
    Pertwee RG (1999) Pharmacology of cannabinoid receptor ligands. Curr Med Chem 6:635–664PubMedGoogle Scholar
  22. 22.
    Batkai S, Osei-Hyiaman D, Pan H, El-Assal O, Rajesh M, Mukhopadhyay P, Hong F, Harvey-White J, Jafri A, Hasko G, Huffman JW, Gao B, Kunos G, Pacher P (2007) Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. FASEB J 21:1788–1800. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Feizi A, Jafari MR, Hamedivafa F, Tabrizian P, Djahanguiri B (2008) The preventive effect of cannabinoids on reperfusion-induced ischemia of mouse kidney. Exp Toxicol Pathol 60:405–410. CrossRefPubMedGoogle Scholar
  24. 24.
    Li Q, Wang F, Zhang YM, Zhou JJ, Zhang Y (2013) Activation of cannabinoid type 2 receptor by JWH133 protects heart against ischemia/reperfusion-induced apoptosis. Cell Physiol Biochem 31:693–702. CrossRefPubMedGoogle Scholar
  25. 25.
    Montecucco F, Lenglet S, Braunersreuther V, Burger F, Pelli G, Bertolotto M, Mach F, Steffens S (2009) CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. J Mol Cell Cardiol 46:612–620. CrossRefPubMedGoogle Scholar
  26. 26.
    Cakir M, Tekin S, Doganyigit Z, Erden Y, Soyturk M, Cigremis Y, Sandal S (2019) Cannabinoid type 2 receptor agonist JWH-133, attenuates Okadaic acid induced spatial memory impairment and neurodegeneration in rats. Life Sci 217:25–33. CrossRefPubMedGoogle Scholar
  27. 27.
    Cakir M, Polat A, Tekin S, Vardi N, Taslidere E, Rumeysa Duran Z, Tanbek K (2015) The effect of dexmedetomidine against oxidative and tubular damage induced by renal ischemia reperfusion in rats. Ren Fail 37:704–708. CrossRefPubMedGoogle Scholar
  28. 28.
    Paller MS, Hoidal JR, Ferris TF (1984) Oxygen free radicals in ischemic acute renal failure in the rat. J Clin Invest 74:1156–1164. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Cakir M, Duzova H, Taslidere A, Orhan G, Ozyalin F (2017) Protective effects of salusin-alpha and salusin-beta on renal ischemia/reperfusion damage and their levels in ischemic acute renal failure. Biotechnol Histochem 92:122–133. CrossRefGoogle Scholar
  30. 30.
    Malek M, Nematbakhsh M (2015) Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Ren Inj Prev 4:20–27. CrossRefPubMedGoogle Scholar
  31. 31.
    Akcay A, Nguyen Q, Edelstein CL (2009) Mediators of inflammation in acute kidney injury. Mediat Inflamm 2009:137072. CrossRefGoogle Scholar
  32. 32.
    Guijarro C, Egido J (2001) Transcription factor-kappa B (NF-kappa B) and renal disease. Kidney Int 59:415–424. CrossRefPubMedGoogle Scholar
  33. 33.
    Zheng Z, Zhao H, Steinberg GK, Yenari MA (2003) Cellular and molecular events underlying ischemia-induced neuronal apoptosis. Drug News Perspect 16:497–503CrossRefGoogle Scholar
  34. 34.
    Ghosh S, Hayden MS (2012) Celebrating 25 years of NF-kappaB research. Immunol Rev 246:5–13. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Marko L, Vigolo E, Hinze C, Park JK, Roel G, Balogh A, Choi M, Wubken A, Cording J, Blasig IE, Luft FC, Scheidereit C, Schmidt-Ott KM, Schmidt-Ullrich R, Muller DN (2016) Tubular epithelial NF-kappaB activity regulates ischemic AKI. J Am Soc Nephrol 27:2658–2669. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Lameire NH, Vanholder R (2004) Pathophysiology of ischaemic acute renal failure. Best Pract Res Clin Anaesthesiol 18:21–36CrossRefGoogle Scholar
  37. 37.
    Wang K, Xie S, Xiao K, Yan P, He W, Xie L (2018) Biomarkers of sepsis-induced acute kidney injury. Biomed Res Int 2018:6937947. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Haase M, Bellomo R, Devarajan P, Schlattmann P, Haase-Fielitz A (2009) Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis 54:1012–1024. CrossRefPubMedGoogle Scholar
  39. 39.
    Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA, Cate RL, Sanicola M (1998) Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem 273:4135–4142CrossRefGoogle Scholar
  40. 40.
    Ritter JK, Li G, Xia M, Boini K (2016) Anandamide and its metabolites: what are their roles in the kidney? Front Biosci (Schol Ed) 8:264–277CrossRefGoogle Scholar
  41. 41.
    Park F, Potukuchi PK, Moradi H, Kovesdy CP (2017) Cannabinoids and the kidney: effects in health and disease. Am J Physiol Ren Physiol 313:F1124–F1132. CrossRefGoogle Scholar
  42. 42.
    Barutta F, Bruno G, Mastrocola R, Bellini S, Gruden G (2018) The role of cannabinoid signaling in acute and chronic kidney diseases. Kidney Int 94:252–258. CrossRefPubMedGoogle Scholar
  43. 43.
    Lim JC, Lim SK, Han HJ, Park SH (2010) Cannabinoid receptor 1 mediates palmitic acid-induced apoptosis via endoplasmic reticulum stress in human renal proximal tubular cells. J Cell Physiol 225:654–663. CrossRefPubMedGoogle Scholar
  44. 44.
    Mukhopadhyay P, Pan H, Rajesh M, Batkai S, Patel V, Harvey-White J, Mukhopadhyay B, Hasko G, Gao B, Mackie K, Pacher P (2010) CB1 cannabinoid receptors promote oxidative/nitrosative stress, inflammation and cell death in a murine nephropathy model. Br J Pharmacol 160:657–668. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Mukhopadhyay P, Baggelaar M, Erdelyi K, Cao Z, Cinar R, Fezza F, Ignatowska-Janlowska B, Wilkerson J, van Gils N, Hansen T, Ruben M, Soethoudt M, Heitman L, Kunos G, Maccarrone M, Lichtman A, Pacher P, Van der Stelt M (2016) The novel, orally available and peripherally restricted selective cannabinoid CB2 receptor agonist LEI-101 prevents cisplatin-induced nephrotoxicity. Br J Pharmacol 173:446–458. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Hu L, Yang C, Zhao T, Xu M, Tang Q, Yang B, Rong R, Zhu T (2012) Erythropoietin ameliorates renal ischemia and reperfusion injury via inhibiting tubulointerstitial inflammation. J Surg Res 176:260–266. CrossRefPubMedGoogle Scholar
  47. 47.
    Kucuk A, Kabadere S, Tosun M, Koken T, Kinaci MK, Isikli B, Erkasap N (2009) Protective effects of doxycycline in ischemia/reperfusion injury on kidney. J Physiol Biochem 65:183–191CrossRefGoogle Scholar
  48. 48.
    Tadagavadi RK, Wang W, Ramesh G (2010) Netrin-1 regulates Th1/Th2/Th17 cytokine production and inflammation through UNC5B receptor and protects kidney against ischemia-reperfusion injury. J Immunol 185:3750–3758. CrossRefPubMedGoogle Scholar
  49. 49.
    Simmons EM, Himmelfarb J, Sezer MT, Chertow GM, Mehta RL, Paganini EP, Soroko S, Freedman S, Becker K, Spratt D, Shyr Y, Ikizler TA (2004) Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney Int 65:1357–1365. CrossRefPubMedGoogle Scholar
  50. 50.
    Murikinati S, Juttler E, Keinert T, Ridder DA, Muhammad S, Waibler Z, Ledent C, Zimmer A, Kalinke U, Schwaninger M (2010) Activation of cannabinoid 2 receptors protects against cerebral ischemia by inhibiting neutrophil recruitment. FASEB J 24:788–798. CrossRefPubMedGoogle Scholar
  51. 51.
    Zarruk JG, Fernandez-Lopez D, Garcia-Yebenes I, Garcia-Gutierrez MS, Vivancos J, Nombela F, Torres M, Burguete MC, Manzanares J, Lizasoain I, Moro MA (2012) Cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection. Stroke 43:211–219. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Faculty of Medicine, Department of PhysiologyUniversity of Yozgat BozokYozgatTurkey
  2. 2.Faculty of Medicine, Department of PhysiologyUniversity of InonuMalatyaTurkey
  3. 3.Faculty of Medicine, Department of Histology and EmbryologyUniversity of Yozgat BozokYozgatTurkey

Personalised recommendations