title: Long noncoding RNA Tug1 regulates mitochondrial bioenergetics in diabetic nephropathy.
abstract: The regulatory roles of long noncoding RNAs (lncRNAs) in transcriptional coactivators are still largely unknown. Here, we have shown that the peroxisome proliferator-activated receptor γ (PPARγ) coactivator α (PGC-1α, encoded by Ppargc1a) is functionally regulated by the lncRNA taurine-upregulated gene 1 (Tug1). Further, we have described a role for Tug1 in the regulation of mitochondrial function in podocytes. Using a murine model of diabetic nephropathy (DN), we performed an unbiased RNA-sequencing (RNA-seq) analysis of kidney glomeruli and identified Tug1 as a differentially expressed lncRNA in the diabetic milieu. Podocyte-specific overexpression (OE) of Tug1 in diabetic mice improved the biochemical and histological features associated with DN. Unexpectedly, we found that Tug1 OE rescued the expression of PGC-1α and its transcriptional targets. Tug1 OE was also associated with improvements in mitochondrial bioenergetics in the podocytes of diabetic mice. Mechanistically, we found that the interaction between Tug1 and PGC-1α promotes the binding of PGC-1α to its own promoter. We identified a Tug1-binding element (TBE) upstream of the Ppargc1a gene and showed that Tug1 binds with the TBE to enhance Ppargc1a promoter activity. These findings indicate that a direct interaction between PGC-1α and Tug1 modulates mitochondrial bioenergetics in podocytes in the diabetic milieu.
authors.forename: Jianyin
authors.initials: J
authors.lastname: Long
authors.forename: Shawn S
authors.initials: SS
authors.lastname: Badal
authors.forename: Zengchun
authors.initials: Z
authors.lastname: Ye
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Ayanga
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Galvan
authors.forename: Nathanael H
authors.initials: NH
authors.lastname: Green
authors.forename: Benny H
authors.initials: BH
authors.lastname: Chang
authors.forename: Paul A
authors.initials: PA
authors.lastname: Overbeek
authors.forename: Farhad R
authors.initials: FR
authors.lastname: Danesh
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000096:biosynthesis* / Q000235:genetics; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D062085:RNA, Long Noncoding; C000619856:long non-coding RNA TUG1, mouse