An Endoplasmic Reticulum Stress-regulated LncRNA Hosting a MicroRNA Megacluster Induces Early Features of Diabetic Nephropathy

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Oct 1

PMID 27686049

Citations 124

Authors

Mitsuo Kato

Mei Wang

Zhuo Chen

Kirti Bhatt

Hyung Jung Oh

Linda Lanting

Supriya Deshpande

Ye Jia

Jennifer Y C Lai

Christopher L OConnor

Yifan Wu

Jeffrey B Hodgin

Robert G Nelson

Markus Bitzer

Rama Natarajan

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Fougeray S, Bouvier N, Beaune P, Legendre C, Anglicheau D, Thervet E . Metabolic stress promotes renal tubular inflammation by triggering the unfolded protein response. Cell Death Dis. 2011; 2:e143. PMC: 3122058. DOI: 10.1038/cddis.2011.26. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Weil E, Fufaa G, Jones L, Lovato T, Lemley K, Hanson R . Effect of losartan on prevention and progression of early diabetic nephropathy in American Indians with type 2 diabetes. Diabetes. 2013; 62(9):3224-31. PMC: 3749332. DOI: 10.2337/db12-1512. View

Lai J, Luo J, OConnor C, Jing X, Nair V, Ju W . MicroRNA-21 in glomerular injury. J Am Soc Nephrol. 2014; 26(4):805-16. PMC: 4378097. DOI: 10.1681/ASN.2013121274. View

Trionfini P, Benigni A, Remuzzi G . MicroRNAs in kidney physiology and disease. Nat Rev Nephrol. 2014; 11(1):23-33. DOI: 10.1038/nrneph.2014.202. View

Iglesias-de la Cruz M, Ziyadeh F, Isono M, Kouahou M, Han D, Kalluri R . Effects of high glucose and TGF-beta1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes. Kidney Int. 2002; 62(3):901-13. DOI: 10.1046/j.1523-1755.2002.00528.x. View

Wang K, Yang Y, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y . A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 2011; 472(7341):120-4. PMC: 3670758. DOI: 10.1038/nature09819. View

Fiore R, Khudayberdiev S, Christensen M, Siegel G, Flavell S, Kim T . Mef2-mediated transcription of the miR379-410 cluster regulates activity-dependent dendritogenesis by fine-tuning Pumilio2 protein levels. EMBO J. 2009; 28(6):697-710. PMC: 2647767. DOI: 10.1038/emboj.2009.10. View

Yamamoto T, Nakamura T, Noble N, Ruoslahti E, Border W . Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci U S A. 1993; 90(5):1814-8. PMC: 45970. DOI: 10.1073/pnas.90.5.1814. View

10.

Ziyadeh F, Hoffman B, Han D, Iglesias-de la Cruz M, Hong S, Isono M . Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci U S A. 2000; 97(14):8015-20. PMC: 16662. DOI: 10.1073/pnas.120055097. View

11.

Cunard R, Sharma K . The endoplasmic reticulum stress response and diabetic kidney disease. Am J Physiol Renal Physiol. 2011; 300(5):F1054-61. PMC: 3094049. DOI: 10.1152/ajprenal.00021.2011. View

12.

Lindow M, Kauppinen S . Discovering the first microRNA-targeted drug. J Cell Biol. 2012; 199(3):407-12. PMC: 3483128. DOI: 10.1083/jcb.201208082. View

13.

Kato M, Natarajan R . Diabetic nephropathy--emerging epigenetic mechanisms. Nat Rev Nephrol. 2014; 10(9):517-30. PMC: 6089507. DOI: 10.1038/nrneph.2014.116. View

14.

Hajarnis S, Patel V, Aboudehen K, Attanasio M, Cobo-Stark P, Pontoglio M . Transcription Factor Hepatocyte Nuclear Factor-1β (HNF-1β) Regulates MicroRNA-200 Expression through a Long Noncoding RNA. J Biol Chem. 2015; 290(41):24793-805. PMC: 4598991. DOI: 10.1074/jbc.M115.670646. View

15.

Yoshida T, Sugiura H, Mitobe M, Tsuchiya K, Shirota S, Nishimura S . ATF3 protects against renal ischemia-reperfusion injury. J Am Soc Nephrol. 2008; 19(2):217-24. PMC: 2396738. DOI: 10.1681/ASN.2005111155. View

16.

Oyadomari S, Mori M . Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2003; 11(4):381-9. DOI: 10.1038/sj.cdd.4401373. View

17.

Novoa I, Gallego J, Ferreira P, Mendez R . Mitotic cell-cycle progression is regulated by CPEB1 and CPEB4-dependent translational control. Nat Cell Biol. 2010; 12(5):447-56. DOI: 10.1038/ncb2046. View

18.

Lopez de Silanes I, Zhan M, Lal A, Yang X, Gorospe M . Identification of a target RNA motif for RNA-binding protein HuR. Proc Natl Acad Sci U S A. 2004; 101(9):2987-92. PMC: 365732. DOI: 10.1073/pnas.0306453101. View

19.

Marselli L, Thorne J, Dahiya S, Sgroi D, Sharma A, Bonner-Weir S . Gene expression profiles of Beta-cell enriched tissue obtained by laser capture microdissection from subjects with type 2 diabetes. PLoS One. 2010; 5(7):e11499. PMC: 2903480. DOI: 10.1371/journal.pone.0011499. View

20.

Wang Q, Wang Y, Minto A, Wang J, Shi Q, Li X . MicroRNA-377 is up-regulated and can lead to increased fibronectin production in diabetic nephropathy. FASEB J. 2008; 22(12):4126-35. PMC: 2614610. DOI: 10.1096/fj.08-112326. View