An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy.
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.
Department of Diabetes Complications and Metabolism, Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Mitsuo
http://orcid.org/0000-0002-1783-1084
M
Kato
Department of Diabetes Complications and Metabolism, Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Mei
M
Wang
Department of Diabetes Complications and Metabolism, Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Zhuo
Z
Chen
Department of Diabetes Complications and Metabolism, Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Kirti
K
Bhatt
Department of Diabetes Complications and Metabolism, Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Hyung Jung
HJ
Oh
Department of Diabetes Complications and Metabolism, Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Linda
L
Lanting
Department of Diabetes Complications and Metabolism, Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Supriya
S
Deshpande
Department of Diabetes Complications and Metabolism, Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Ye
Y
Jia
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Jennifer Y C
JY
Lai
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Christopher L
CL
O'Connor
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
YiFan
Y
Wu
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Jeffrey B
JB
Hodgin
Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85014, USA.
Robert G
RG
Nelson
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Markus
M
Bitzer
Department of Diabetes Complications and Metabolism, Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Rama
R
Natarajan
Cell Death Dis. 2011 Apr 14;2:e143
21490675
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
16199517
Diabetes. 2013 Sep;62(9):3224-31
23545707
J Am Soc Nephrol. 2015 Apr;26(4):805-16
25145934
Nat Rev Nephrol. 2015 Jan;11(1):23-33
25385286
Kidney Int. 2002 Sep;62(3):901-13
12164872
Nature. 2011 Apr 7;472(7341):120-4
21423168
EMBO J. 2009 Mar 18;28(6):697-710
19197241
Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1814-8
7680480
Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8015-20
10859350
Am J Physiol Renal Physiol. 2011 May;300(5):F1054-61
21345978
J Cell Biol. 2012 Oct 29;199(3):407-12
23109665
Nat Rev Nephrol. 2014 Sep;10(9):517-30
25003613
J Biol Chem. 2015 Oct 9;290(41):24793-805
26292219
J Am Soc Nephrol. 2008 Feb;19(2):217-24
18235102
Cell Death Differ. 2004 Apr;11(4):381-9
14685163
Nat Cell Biol. 2010 May;12(5):447-56
20364142
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2987-92
14981256
PLoS One. 2010 Jul 13;5(7):e11499
20644627
FASEB J. 2008 Dec;22(12 ):4126-35
18716028
Diabetes. 2005 Jun;54(6):1626-34
15919782
Nucleic Acids Res. 2014 Jul;42(12):7819-32
24861627
Diabetes. 2005 Jul;54(7):1976-84
15983197
Cell. 2001 Dec 28;107(7):881-91
11779464
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3432-7
17360662
Cell. 1989 Apr 7;57(1):103-13
2467742
Diabetes. 1995 Oct;44(10):1139-46
7556948
Annu Rev Biochem. 2010;79:351-79
20533884
J Am Soc Nephrol. 2012 Mar;23 (3):458-69
22223877
Diabetes. 2013 Sep;62(9):3151-62
23649518
Am J Pathol. 2010 May;176(5):2163-76
20363923
Biochem Biophys Res Commun. 2008 Jun 13;370(4):651-6
18420027
Am J Physiol Renal Physiol. 2014 Apr 15;306(8):F916-25
24452638
Sci Signal. 2013 Jun 04;6(278):ra43
23737551
EMBO Mol Med. 2014 Jun 16;6(7):851-64
24935956
Cell Metab. 2014 Jan 7;19(1):135-45
24374217
Nat Commun. 2015 Mar 10;6:6496
25754093
Annu Rev Pathol. 2011;6:395-423
21261520
Intern Med. 2009;48(18):1615-20
19755763
J Clin Invest. 2011 Jun;121(6):2181-96
21606597
Kidney Int. 2011 Aug;80(4):358-68
21389977
Cell. 1996 Jun 28;85(7):947-50
8674122
Nature. 2005 Dec 1;438(7068):685-9
16258535
Sci Transl Med. 2012 Feb 15;4(121):121ra18
22344686
J Am Soc Nephrol. 2014 Sep;25(9):2067-78
24676635
J Biol Chem. 2006 Apr 7;281(14):9650-8
16431915
Diabetes. 2006 Jan;55(1):225-33
16380497
RNA. 2009 Jun;15(6):1059-66
19383768
PLoS One. 2013 Oct 25;8(10):e77468
24204837
Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4221-6
22371589
J Biol Chem. 2012 May 4;287(19):15672-83
22431733
J Biol Chem. 2011 Apr 1;286(13):11837-48
21310958
Circ Res. 2014 Apr 25;114(9):1389-97
24602777
Nat Cell Biol. 2009 Jul;11(7):881-9
19543271
J Clin Invest. 2014 Jun;124(6):2333-40
24892707
Nucleic Acids Res. 2010 Dec;38(22):8338-47
20716515
Nature. 2007 Aug 9;448(7154):718-22
17687328
J Am Soc Nephrol. 2012 Dec;23 (12 ):2012-23
23160513
J Am Soc Nephrol. 2008 Nov;19(11):2225-36
18776125
Cell. 2009 Jan 23;136(2):215-33
19167326
Mol Cell. 2003 Jan;11(1):113-26
12535526
Diabetologia. 2013 Mar;56(3):663-74
23292313
Mol Cell Biol. 1997 Nov;17(11):6700-7
9343434
Cell. 2008 May 2;133(3):403-14
18455982
Sci Transl Med. 2015 Dec 2;7(316):316ra193
26631632
Ann N Y Acad Sci. 2015 Sep;1353:72-88
25877817
Diabetologia. 2014 Aug;57(8):1726-36
24908566
J Am Soc Nephrol. 2015 Dec;26(12 ):3162-78
26038526