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An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy

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  • Mitsuo Kato

    (Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope)

  • Mei Wang

    (Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope)

  • Zhuo Chen

    (Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope)

  • Kirti Bhatt

    (Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope)

  • Hyung Jung Oh

    (Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope)

  • Linda Lanting

    (Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope)

  • Supriya Deshpande

    (Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope)

  • Ye Jia

    (Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope)

  • Jennifer Y.C. Lai

    (University of Michigan)

  • Christopher L. O’Connor

    (University of Michigan)

  • YiFan Wu

    (University of Michigan)

  • Jeffrey B. Hodgin

    (University of Michigan)

  • Robert G. Nelson

    (Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health)

  • Markus Bitzer

    (University of Michigan)

  • Rama Natarajan

    (Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope)

Abstract

It is important to find better treatments for diabetic nephropathy (DN), a debilitating renal complication. Targeting early features of DN, including renal extracellular matrix accumulation (ECM) and glomerular hypertrophy, can prevent disease progression. Here we show that a megacluster of nearly 40 microRNAs and their host long non-coding RNA transcript (lnc-MGC) are coordinately increased in the glomeruli of mouse models of DN, and mesangial cells treated with transforming growth factor-β1 (TGF- β1) or high glucose. Lnc-MGC is regulated by an endoplasmic reticulum (ER) stress-related transcription factor, CHOP. Cluster microRNAs and lnc-MGC are decreased in diabetic Chop−/− mice that showed protection from DN. Target genes of megacluster microRNAs have functions related to protein synthesis and ER stress. A chemically modified oligonucleotide targeting lnc-MGC inhibits cluster microRNAs, glomerular ECM and hypertrophy in diabetic mice. Relevance to human DN is also demonstrated. These results demonstrate the translational implications of targeting lnc-MGC for controlling DN progression.

Suggested Citation

  • Mitsuo Kato & Mei Wang & Zhuo Chen & Kirti Bhatt & Hyung Jung Oh & Linda Lanting & Supriya Deshpande & Ye Jia & Jennifer Y.C. Lai & Christopher L. O’Connor & YiFan Wu & Jeffrey B. Hodgin & Robert G. N, 2016. "An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy," Nature Communications, Nature, vol. 7(1), pages 1-16, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12864
    DOI: 10.1038/ncomms12864
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