Journal of Molecular Medicine

, Volume 92, Issue 7, pp 779–792 | Cite as

Cannabinoid receptor 1 disturbance of PPARγ2 augments hyperglycemia induction of mesangial inflammation and fibrosis in renal glomeruli

  • Chun-Liang Lin
  • Yung-Chien Hsu
  • Pei-Hsien Lee
  • Chen-Chou Lei
  • Jeng-Yi Wang
  • Yu-Ting Huang
  • Shao-Yu Wang
  • Feng-Sheng Wang
Original Article

Abstract

Intensive fibrosis in the glomerular microenvironment is a prominent feature of diabetic nephropathy. Cannabinoid receptor 1 (CB1R) reportedly mediates diabetes-induced renal injury. However, studies on the molecular events underlying CB1R promotion of renal dysfunction are limited. This study is undertaken to investigate whether CB1R signaling via Ras or PPARγ pathway regulates mesangial fibrosis in diabetic kidneys. In streptozotocin-induced diabetic rats, hyperglycemia induced glomerular hypertrophy and fibrosis in association with increased IL-1β, fibronectin, and CB1R expressions and reduced PPARγ2 signaling. CB1R transgenic mice gained kidney weight, and renal glomeruli strongly displayed IL-1β and fibrotic matrices. Disruption of CB1R by antisense oligonucleotides or inverse agonist AM251 restored PPARγ2 signaling and reduced the promotional effects of hyperglycemia on the expression of fibrogenic transcription factor c-Jun, inflammation regulator SOCS3, proinflammatory cytokines, and accumulation of fibrotic matrix. PPARγ agonist rosiglitazone reduced the hyperglycemia-mediated enhancement of CB1R signaling, inflammation, and glomerular fibrosis in diabetic animals. In vitro, CB1R antagonism restored PPARγ2 action and reduced the promotional effects of high glucose on Ras, ERK, c-Jun, SOCS3 signaling, IL-1β, and fibronectin expression in renal mesangial cells. Activation of PPARγ2 reduced the high glucose-induced CB1R expression in mesangial cells. Taken together, CB1R signaling contributes to the hyperglycemia disturbance of PPARγ2 signaling and increases inflammatory cytokine secretion and fibrotic matrix deposition in renal glomeruli. CB1R mediates the hyperglycemia-induced inflammation and fibrosis in mesangial cells by regulating Ras, ERK, and PPARγ2 signaling. CB1R blockade has a therapeutic potential to reduce the deleterious actions of hyperglycemia on renal glomerular integrity.

Key message

  • Hyperglycemia increases glomerular fibrosis, inflammation, and CB1R signaling.

  • CB1R signaling promotes fibrosis and inflammation of renal tissue.

  • Loss of CB1R function alleviates diabetes-mediated renal deterioration.

  • PPARγ agonist decreases CB1R expression in diabetic renal glomeruli.

  • Ras and ERK mediated CB1R promotion of fibrosis matrix deposition in mesangial cells.

Keywords

Diabetic nephropathy Cannabinoid receptor type 1 PPARγ2 signaling Renal fibrosis 

Supplementary material

109_2014_1125_MOESM1_ESM.doc (1.1 mb)
Supplemental data 3Effect of high glucose on the level of phosphorylated p38 and phosphorylated JNK in mesangial cells. High glucose did not significantly change the levels of phosphorylated p38, p38, phosphorylated JNK or JNK in mesangial cells exposed to high glucose for 4–48 h. Data are expressed as mean ± SEM calculated from at least three experiments. (DOC 1122 kb)

References

  1. 1.
    Emerging Risk Collaboration. Seshasai SR, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, Whicncup PH, Mukamal KJ, Gillum RF, Holme I et al (2011) Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 364:829–841CrossRefGoogle Scholar
  2. 2.
    Schena FP, Gesualdo L (2005) Pathogenetic mechanisms of diabetic nephropathy. J Am Soc Nephrol 16:30–33CrossRefGoogle Scholar
  3. 3.
    Li J, Zhu H, Shen E, Wan L, Amold JM, Peng T (2010) Deficiency of rac1 blocks NADPH oxidase activation, inhibits endoplasmic reticulum stress, and reduces myocardial remodeling in a mouse model of type 1 diabetes. Diabetes 69:2033–2042CrossRefGoogle Scholar
  4. 4.
    Darisipudi MN, Kulkarni OP, Sayyed SG, Ryu M, Migliorini A, Sagrinati C, Parente E, Vater A, Eulberg D, Klussmann S et al (2011) Dual blockade of the homeostatic chemokines CXCL12 and the pro-inflammatory chemokine CCL2 has additative protective effects on diabetic kidney disease. Am J Pathol 179:116–124PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Despres JP, Golay A, Sjostrom L (2005) Rimonabant in Obesity-Lipid Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353:2121–2134PubMedCrossRefGoogle Scholar
  6. 6.
    Idris AI, Van’t Hof RJ, Greig IR, Ridge SA, Baker D, Ross RA, Ralston SH (2005) Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med 11:774–779PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Bromberg KD, Ma’ayan A, Neves SR, Iyengar R (2008) Design logic of a cannabinoid receptor signaling network that triggers neurite outgrowth. Science 320:903–909PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Domenicali M, Caraceni P, Glannone F, Pertosa AM, Principe A, Zambruni A, Trevisani F, Crod T, Bernadi M (2009) Cannabinoid type 1 receptor antagonism delays ascites formation in rats with cirrhosis. Gastroenterology 137:341–349PubMedCrossRefGoogle Scholar
  9. 9.
    Barutta F, Corbelli A, Mastrocola R, Gambino R, Di Marzo V, Pinach S, Pastalsi MP, Perin PC, Cruden G (2010) Cannabinoid receptor 1 blockade ameliorates albuminuria in experimental diabetic nephropathy. Diabetes 59:1046–1054PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Lim JC, Lim SK, Han HJ, Park SH (2010) Cannabinoid receptor 1 mediates palmitic acid-induced via endoplasmic reticulum stress in human renal proximal tubular cells. J Cell Physiol 225:654–663PubMedCrossRefGoogle Scholar
  11. 11.
    Mukhopadhyay P, Pan H, Rajesh M, Batkai S, Patel V, Harvey-White J, Mukhopadhyay B, Hasko G, Gao B, Mackie K et al (2010) CB1R cannabinoid receptors promotes oxidative/nitrosative stress, inflammation and cell death in a murine nephropathy model. Br J Pharmacol 160:657–668PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Lim MP, Devi LA, Rozenfeld R (2011) Cannabidiol causes activated hepatic stellate cell death through a mechanism of endoplasmic reticulum stress-induced apoptosis. Cell Death Dis 2:e170PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Rajesh M, Barkai S, Kechrid M, Muckhopadhyay P, Lee WS, Horvath B, Holovac E, Cinar R, Liaudet L, Mackie K et al (2012) Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. Diabetes 61:716–727PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Nicholas SB, Liu J, Kim J, Ren Y, Collins AR, Nguyen L, Hsueh WA (2010) Critical role for osteoponitin in diabetic nephropathy. Kidney Int 77:588–600PubMedCrossRefGoogle Scholar
  15. 15.
    Yang HC, Deleuze S, Zuo Y, Potthoff SA, Ma LJ, Fogo AB (2009) The PPARgamma agonist pioglitazone ameliorates aging-related progressive renal injury. J Am Soc Nephrol 20:2380–2388PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Du H, Chen X, Zhang J, Chen C (2011) Inhibition of COX2 expression by endocannabinoid 2-arachidonoylglycerol is mediated via PPAR-γ. Br J Pharmacol 163:1533–1549PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Rajesh M, Mukhopadhyay P, Hasko G, Pacher P (2008) Cannabinoid CB1R receptor inhibition decreases vascular smooth muscle migration and proliferation. Biochem Biophys Res Commun 377:1248–1252PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Lin CL, Wang FS, Kuo YR, Huang YT, Huang HC, Sun YC, Kuo YH (2006) Ras modulation of superoxide activates ERK-dependent fibronectin expression in diabetes-induced renal injuries. Kidney Int 69:1593–1600PubMedCrossRefGoogle Scholar
  19. 19.
    Hsiao YC, Chang HH, Tsai CY, Jong TJ, Horng LS, Lin SF, Tsai TF (2004) Coat color-tagged green mouse with EGFP expressed from the RNA polymerase II promoter. Genesis 39:122–129PubMedCrossRefGoogle Scholar
  20. 20.
    Lin CL, Wang CY, Huang YT, Kuo YH, Surendran K, Wang FS (2006) Wnt/β-catenin signaling modulates survival of high glucose-stressed glomerular mesangial cells. J Am Soc Nephrol 17:2812–2820PubMedCrossRefGoogle Scholar
  21. 21.
    Lin CL, Wang JY, Ko JY, Huang YT, Kuo YH, Wang FS (2010) Dickkopf-1 promotes hyperglycemia-induced accumulation of mesangial matrix and renal dysfunction. J Am Soc Nephrol 21:124–135PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    El-Remessy AB, Rajesh M, Mujhopadhyay P, Horvath B, Patel V, Al-Gayyar MM, Pillai BA, Pacher P (2011) Cannabinoid receptor activation contributes to vascular inflammation and cell death in a mouse model of diabetic retinopathy and a human retinal cell line. Diabetologia 54:1567–1578PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Ko JY, Wu RW, Kuo SJ, Chen MW, Yeh DW, Ke HC, Wu SL, Wang FS (2012) Cannabinoid receptor 1 mediates glucocorticoid-induced bone loss by perturbing bone acquisition and marrow adipogenesis. Arthritis Rheum 64:1204–1214PubMedCrossRefGoogle Scholar
  24. 24.
    Servettaz A, Kavian N, Nicco C, Deveaux V, Chéreau C, Wang A, Zimmer A, Lotersztajn S, Weill B, Batteux F (2010) Targeting of the cannabinoid pathway limits the development of fibrosis and autoimmunity in a mouse model of systemic sclerosis. Am J Pathol 177:187–196PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Tallett AJ, Blundell JE, Rodgers JR (2007) Acute anorectic response to cannabinoid CB1R receptor antagonist/inverse agonist AM251 in rats: indirect behavior mediation. Behav Pharmacol 18:591–600PubMedCrossRefGoogle Scholar
  26. 26.
    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 60:2386–2396PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Hwang I, Lee J, Huh JY, Park J, Lee HB, Ho YS, Ha H (2012) Catalase deficiency accelerates diabetes renal injury through peroxisomal dysfunction. Diabetes 61:728–738PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Declèves AE, Mathew AV, Cundard R, Sharma K (2011) AMPK mediates the initiation of kidney disease induced by a high fat diet. J Am Soc Nephrol 22:1846–1855PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Zivadeh FN, Wolf G (2008) Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev 4:39–45CrossRefGoogle Scholar
  30. 30.
    Pisanti S, Picardi P, Prota L, Proto MC, Laezza C, McGuire PG, Morbidelli L, Gazzerro P, Ziche M, Das A et al (2011) Genetic and pharmacologic inactivation of cannabinoid CB1R receptor inhibits angiogenesis. Blood 117:5541–5550PubMedCrossRefGoogle Scholar
  31. 31.
    Tedesco L, Valerio A, Dossena M, Cardile A, Ragni M, Pagano C, Pagotto U, Carruba MO, Vettor R, Nisoli E (2010) Cannabinoid receptor stimulation impairs mitochondrial biogenesis in mouse white adipose tissue, muscle, and liver: the role of eNOS, p38 MAPK, and AMPK pathways. Diabetes 59:2826–2836PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Huang J, Siragy HM (2010) Regulation of (pro)rennin receptor expression by glucose-induced mitogen-activated protein kinase, nuclear factor-kappaB, and activator protein-1 signaling pathways. Endocrinology 151:3317–3325PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Idris AI, Sophocleous A, Lando-Bassonga E, Canals M, Milligan G, Baker D, van’t Hof RJ, Ralston SH (2009) Cannabinoid receptor type 1 protects against age-related osteoporosis by regulating osteoblast and adipocyte differentiation in marrow stromal cells. Cell Metab 10:139–147PubMedCrossRefGoogle Scholar
  34. 34.
    O’Sullivan SE (2007) Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol 152:576–582PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Chun-Liang Lin
    • 1
    • 4
    • 5
  • Yung-Chien Hsu
    • 1
  • Pei-Hsien Lee
    • 1
  • Chen-Chou Lei
    • 1
  • Jeng-Yi Wang
    • 2
  • Yu-Ting Huang
    • 1
  • Shao-Yu Wang
    • 1
  • Feng-Sheng Wang
    • 3
    • 6
    • 7
  1. 1.Departments of NephrologyChang Gung Memorial HospitalChiayiTaiwan
  2. 2.Department of Colorectal SurgeryChang Gung Memorial HospitalTaipeiTaiwan
  3. 3.Department of Medical ResearchKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
  4. 4.Kidney Research CenterChang Gung Memorial HospitalTaipeiTaiwan
  5. 5.School of Traditional Chinese MedicineChang Gung University College of MedicineTaoyuanTaiwan
  6. 6.Center for Translational Research in Biomedical SciencesKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
  7. 7.Graduate Institute of Clinical Medical ScienceChang Gung University College of MedicineTaoyuanTaiwan

Personalised recommendations