An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy.
Mitsuo KatoMei WangZhuo ChenKirti BhattHyung Jung OhLinda LantingSupriya DeshpandeYe JiaJennifer Y C LaiChristopher L O'ConnorYiFan WuJeffrey B HodginRobert G NelsonMarkus BitzerRama NatarajanPublished in: Nature communications (2016)
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.
Keyphrases
- diabetic nephropathy
- long non coding rna
- extracellular matrix
- transforming growth factor
- endoplasmic reticulum stress
- high glucose
- induced apoptosis
- endothelial cells
- transcription factor
- endoplasmic reticulum
- poor prognosis
- cancer therapy
- diffuse large b cell lymphoma
- epithelial mesenchymal transition
- mouse model
- rna seq
- cell proliferation
- dna methylation
- skeletal muscle
- cell cycle arrest
- genome wide
- metabolic syndrome
- genome wide identification
- drug delivery
- induced pluripotent stem cells