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Inhibition of interleukin-6 on matrix protein production by glomerular mesangial cells and its pathway involved

Chaudhari, Sarika and Shotorbani, Parisa Yazdizadeh and Tao, Yu and Davis, Mark E. and Mallet, Robert T. and Ma, Rong (2020) Inhibition of interleukin-6 on matrix protein production by glomerular mesangial cells and its pathway involved. American Journal of Physiology - Renal Physiology, 318 (6). F1478-F1488. ISSN 1931-857X. doi:10.1152/ajprenal.00043.2020.

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Activation of immunological pathways and disturbances of extracellular matrix (ECM) dynamics are important contributors to the pathogenesis of chronic kidney diseases. Glomerular mesangial cells (MCs) are critical for homeostasis of glomerular ECM dynamics. Interleukin-6 (IL-6) can act as a pro/anti-inflammatory agent relative to cell types and conditions. This study investigated whether IL-6 influences ECM protein production by MCs and the regulatory pathways involved. Experiments were carried out in cultured human MCs (HMCs) and in mice. We found that overexpression of IL-6 and its receptor decreased the abundance of fibronectin and collagen type IV in MCs. ELISA and immunoblot analysis demonstrated that thapsigargin [an activator of store-operated Ca²⁺ entry (SOCE)], but not the endoplasmic reticulum stress inducer tunicamycin, significantly increased IL-6 content. This thapsigargin effect was abolished by GSK-7975A, a selective inhibitor of SOCE, and by silencing Orai1 (the channel protein mediating SOCE). Furthermore, inhibition of NF-κB pharmacologically and genetically significantly reduced SOCE-induced IL-6 production. Thapsigargin also stimulated nuclear translocation of the p65 subunit of NF-κB. Moreover, MCs overexpressing IL-6 and its receptor in HMCs increased the content of the glucagon-like peptide-1 receptor (GLP-1R), and IL-6 inhibition of fibronectin was attenuated by the GLP-1R antagonist exendin 9–39. In agreement with the HMC data, specific knockdown of Orai1 in MCs using the targeted nanoparticle delivery system in mice significantly reduced glomerular GLP-1R levels. Taken together, our results suggest a novel SOCE/NF-κB/IL-6/GLP-1R signaling pathway that inhibits ECM protein production by MCs.

Item Type:Article
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Davis, Mark E.0000-0001-8294-1477
Additional Information:© 2020 American Journal of Physiology-Renal Physiology. Received 30 January 2020; Accepted 5 May 2020; Published online 5 June 2020; Published in print 1 June 2020. We thank GlaxoSmithKline (Brentford, UK) for providing GSK-7975A compound and Dr. S. Rose-John (Christian-Albrechts-University, Kiel, Germany) for providing the expression plasmid pCDM8-H-IL-6. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant 5-RO1-DK-079968-01 (to R. Ma) and by American Heart Association Southwestern Affiliate Postdoctoral Fellowship 20POST35210685 (to S. Chaudhari). No conflicts of interest, financial or otherwise, are declared by the author(s). Author Contributions: S.C. and R.M. conceived and designed research; S.C. performed experiments; S.C. and R.M. analyzed data; S.C., P.Y.S., and R.M. interpreted results of experiments; S.C. and R.M. prepared figures; S.C. drafted manuscript; P.Y.S., Y.T., M.E.D., R.T.M., and R.M. edited and revised manuscript; S.C., P.Y.S., Y.T., M.E.D., R.T.M., and R.M. approved final version of manuscript.
Funding AgencyGrant Number
American Heart Association20POST35210685
Subject Keywords:extracellular matrix; glucagon-like peptide-1 receptor; interleukin-6; mesangial cells; nuclear factor-κB; Orai1; tore-operated calcium entry
Issue or Number:6
Record Number:CaltechAUTHORS:20200518-150718789
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Official Citation:Inhibition of interleukin-6 on matrix protein production by glomerular mesangial cells and the pathway involved Sarika Chaudhari, Parisa Yazdizadeh Shotorbani, Yu Tao, Mark E. Davis, Robert T. Mallet, and Rong Ma American Journal of Physiology-Renal Physiology 2020 318:6, F1478-F1488; doi: 10.1152/ajprenal.00043.2020
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103289
Deposited By: Tony Diaz
Deposited On:18 May 2020 23:11
Last Modified:16 Nov 2021 18:20

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