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.
Highlights
It is important to find better treatments for diabetic nephropathy (DN), a debilitating renal complication
Genome organization shows that the megacluster (MGC) is hosted by a lncRNA, termed ‘lnc-MGC’, 3’ region of which overlaps with Mirg and middle region with Gm2922, other ncRNAs (Fig. 1c and Supplementary Fig. 1). miR-379 is located at the 50 end, miR-494 and miR-495 in the middle, and miR-377 downstream (Fig. 1c)
transforming growth factor-b1 (TGF-b1) and high glucose (HG) significantly increased the expression of miR-379, miR-494, miR-495 and miR-377 as well as lnc-MGC, but not miR-882, compared with serum depleted (SD) or normal glucose (NG) controls respectively in cultured mouse mesangial cells (MCs) (MMC; Fig. 2d)
Summary
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. A chemically modified oligonucleotide targeting lnc-MGC inhibits cluster microRNAs, glomerular ECM and hypertrophy in diabetic mice. Inhibition of key miRNAs by chemically modified antisense oligonucleotides or by genetic knockout (KO) attenuated early manifestations of DN in mice (ECM accumulation and glomerular hypertrophy) and albuminuria (a later feature of DN)[2,6,10,11,12,16,17,18,19,20,21]. Inhibition of the host transcript decreased the expression of the cluster miRNAs, and attenuated early features of DN in vitro in MCs, and in vivo in mice
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