PGC1α Is Required for the Renoprotective Effect of lncRNA Tug1 In Vivo and Links Tug1 With Urea Cycle Metabolites

Authors

Li Li
Jianyin Long
Koki Mise
Daniel L Galvan
Paul A Overbeek
Lin Tan
Shwetha V Kumar
Wai Kin Chan
Phillip L Lorenzi
Benny H Chang
Farhad R Danesh

Publication Date

8-10-2021

Journal

Cell Reports

DOI

10.1016/j.celrep.2021.109510

PMID

34380028

PMCID

PMC8369494

PubMedCentral® Posted Date

8-17-2021

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Arginase, Diabetic Nephropathies, Disease Progression, Gene Deletion, Kidney, Metabolome, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Podocytes, Protective Agents, RNA, Long Noncoding, Urea, Mice

Abstract

lncRNA taurine-upregulated gene 1 (Tug1) is a promising therapeutic target in the progression of diabetic nephropathy (DN), but the molecular basis of its protection remains poorly understood. Here, we generate a triple-mutant diabetic mouse model coupled with metabolomic profiling data to interrogate whether Tug1 interaction with peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) is required for mitochondrial remodeling and progression of DN in vivo. We find that, compared with diabetic conditional deletion of Pgc1α in podocytes alone (db/db; Pgc1αPod-f/f), diabetic Pgc1α knockout combined with podocyte-specific Tug1 overexpression (db/db; TugPodTg; Pgc1αPod-f/f) reverses the protective phenotype of Tug1 overexpression, suggesting that PGC1α is required for the renoprotective effect of Tug1. Using unbiased metabolomic profiling, we find that altered urea cycle metabolites and mitochondrial arginase 2 play an important role in Tug1/PGC1α-induced mitochondrial remodeling. Our work identifies a functional role of the Tug1/PGC1α axis on mitochondrial metabolic homeostasis and urea cycle metabolites in experimental models of diabetes.

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