The long noncoding RNA Tug1 connects metabolic changes with kidney disease in podocytes

Abstract

An increasing amount of evidence suggests that metabolic alterations play a key role in chronic kidney disease (CKD) pathogenesis. In this issue of the JCI, Long et al. report that the long noncoding RNA (lncRNA) taurine-upregulated 1 (Tug1) contributes to CKD development. The authors show that Tug1 regulates mitochondrial function in podocytes by epigenetic targeting of expression of the transcription factor PPARγ coactivator 1α (PGC-1α, encoded by Ppargc1a). Transgenic overexpression of Tug1 specifically in podocytes ameliorated diabetes-induced CKD in mice. Together, these results highlight an important connection between lncRNA-mediated metabolic alterations in podocytes and kidney disease development.

Figure 1. lncRNAs can interfere with gene function at multiple levels.

Studies have described a range of mechanisms by which lncRNAs regulate their targets. In the cell nucleus, lncRNAs can regulate transcription by recruiting chromatin-modifying complexes and transcriptional factors to silence or enhance target gene expression. Additionally, some lncRNAs regulate gene expression by influencing pre-mRNA splicing. In the cytosol, lncRNAs can regulate mRNA expression by altering mRNA stability, mRNA translation, or by competing for microRNA binding. ICR1,Interfering Crick RNA 1; PWR1, Promoting Watson RNA1; SRA, Steroid receptor RNA Activator PANDA, P21 associated ncRNA DNA damage activated, PANDA antisense RNA GAS5, Growth arrest-specific 5; TF, Transcription factor; XIST, X-inactive specific transcript; HOTAIR, HOX transcript antisense RNA; KCNQ1OT1, KCNQ1 overlapping transcript 1; PRC2, Polycomb Repressive Complex 2; HOTTIP, HOXA transcript at the distal tip; KLK3e, Kallikrein-related peptidase 3 eRNA; SF, Splicing factor; STAU1, Staufen Double-Stranded RNA Binding Protein 1; TINCR, Tissue Differentiation-Inducing Non-Protein Coding RNA; CDR1as, Cerebellar degeneration-related protein 1 Antisense RNA; LINCMD1, long intergenic non-protein coding RNA, muscle differentiation 1.

Figure 2. Proper mitochondrial function is essential for podocyte health in diabetes.

Tug1 expression is decreased in diabetic podocytes. Tug1 regulates PGC-1α expression by epigenetic targeting. Decreased PGC-1α levels results in structural and functional mitochondrial changes. Impaired mitochondrial function will cause energy depletion, increased ROS generation, and, ultimately, the development of diabetic kidney disease. DKD, diabetic kidney disease; NOX4, NAPDH oxidase 4.