期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 126, 期 11, 页码 4205-4218出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI87927
关键词
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资金
- NIH [RO1 DK091310, RO1 DK078900]
- NCI Cancer Center support grant [P30CA16672]
- UT-MDACC Sequencing and Microarray Facility [CA016672 SMF]
- [CA16672]
The regulatory roles of long noncoding RNAs (IncRNAs) in transcriptional coactivators are still largely unknown. Here, we have shown that the peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator alpha (PGC-1 alpha, encoded by Ppargc1a) is functionally regulated by the IncRNA taurine-upregulated gene 1 (Tug1). Further, we have described a role for Tug1 in the regulation of mitochondria! 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 IncRNA 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-1a 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 Tugl and PGC-1 alpha promotes the binding of PGC-1 alpha to its own promoter. We identified a Tug1-binding element (TBE) upstream of the Ppargcla gene and showed that Tugl binds with the TBE to enhance Ppargcla promoter activity. These findings indicate that a direct interaction between PGC-1 alpha and Tugl modulates mitochondria! bioenergetics in podocytes in the diabetic milieu.
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