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

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. Nelson, Markus Bitzer and Rama Natarajan ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12864

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