Long noncoding RNA Tug1 regulates mitochondrial bioenergetics in diabetic nephropathy

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.