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

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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.

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Acknowledgments

This work was supported in part by grants NSC101-2314-B-115-MY3 from the National Science Council, NHRI-EX99-9942SI and NHRI-EX102-10140EI from the National Health Research Institute, and CMRPG6G0031 and CMRPG6B0401 from Chang Gung Memorial Hospital, Taiwan. The authors thank the Center for Laboratory Animals, Kaohsiung Chang Gung Memorial Hospital, for the use of their facilities.

Conflict of interest

The authors have nothing to disclose.

Open access

This article is distributed under the terms of the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the sources are credited.

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Authors and Affiliations

  1. Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan

    Chun-Liang Lin, Yung-Chien Hsu, Pei-Hsien Lee, Chen-Chou Lei, Yu-Ting Huang & Shao-Yu Wang

  2. Department of Colorectal Surgery, Chang Gung Memorial Hospital, Taipei, Taiwan

    Jeng-Yi Wang

  3. Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung District, Kaohsiung, 833, Taiwan

    Feng-Sheng Wang

  4. Kidney Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan

    Chun-Liang Lin

  5. School of Traditional Chinese Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan

    Chun-Liang Lin

  6. Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan

    Feng-Sheng Wang

  7. Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, Taoyuan, Taiwan

    Feng-Sheng Wang

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  1. Chun-Liang Lin
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Correspondence to Feng-Sheng Wang.

Additional information

Chun-Liang Lin, Yung-Chien Hsu, Chen-Chou Lei and Pei-Hsien Lee contributed equally.

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Supplemental data 3

Effect 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)

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Lin, CL., Hsu, YC., Lee, PH. et al. Cannabinoid receptor 1 disturbance of PPARγ2 augments hyperglycemia induction of mesangial inflammation and fibrosis in renal glomeruli. J Mol Med 92, 779–792 (2014). https://doi.org/10.1007/s00109-014-1125-6

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  • DOI: https://doi.org/10.1007/s00109-014-1125-6

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