@article{5eb3097f30a345a9af841841c87b2ed0,
title = "PGC1α is required for the renoprotective effect of lncRNA Tug1 in vivo and links Tug1 with urea cycle metabolites",
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.",
keywords = "PGC1α, RNA, Tug1, diabetic nephropathy, lncRNA, mitochondrial metabolites, podocytes",
author = "Li Li and Jianyin Long and Koki Mise and Galvan, {Daniel L.} and Overbeek, {Paul A.} and Lin Tan and Kumar, {Shwetha V.} and Chan, {Wai Kin} and Lorenzi, {Phillip L.} and Chang, {Benny H.} and Danesh, {Farhad R.}",
note = "Funding Information: This work was supported by National Institutes of Health grants R01DK078900 (to F.R.D.) and R01DK091310 (to F.R.D.). L.L. is supported by a scholarship from the China Scholarship Council (202006370196). S.V.K. receives a Predoctoral Fellowship from UTHealth Innovation for Cancer Prevention Research Training Program (RP160015;) (Disclaimer: the content is solely the responsibility of the authors and does not necessarily represent the official views of the Cancer Prevention and Research Institute of Texas). The UT-MDACC Metabolomics Core Facility is supported by Cancer Prevention and Research Institute of Texas grant RP130397 and NIH grants S10OD012304-01 and P30CA016672. We acknowledge the High Resolution Electron Microscopy Facility (NIH grant P30CA016672) at UT-MDACC for performing the TEM studies. We are also grateful to the Flow Cytometry and Cellular Imaging Core Facility (FCCICF) (NCI grant P30CA16672) at UT-MDACC for advice and help in flow cytometry experiments. L.L. and J.L. performed experiments, analyzed the data, and wrote the manuscript. K.M. and D.L.G. helped perform experiments and analyze data. L.T. and S.V.K. analyzed metabolomic data. W.K.C. designed and helped perform Seahorse experiments. P.L.L. designed the metabolomic experiments and analyzed the results. P.A.O. helped with the initial design of the project. B.H.C. helped with the design of the study and edited the manuscript. F.R.D. oversaw the experiments, wrote the initial draft, and provided guidance on overall project design. All authors reviewed and edited the manuscript. The authors declare no competing interests. Funding Information: This work was supported by National Institutes of Health grants R01DK078900 (to F.R.D.) and R01DK091310 (to F.R.D.). L.L. is supported by a scholarship from the China Scholarship Council ( 202006370196 ). S.V.K. receives a Predoctoral Fellowship from UTHealth Innovation for Cancer Prevention Research Training Program ( RP160015 ;) (Disclaimer: the content is solely the responsibility of the authors and does not necessarily represent the official views of the Cancer Prevention and Research Institute of Texas ). The UT-MDACC Metabolomics Core Facility is supported by Cancer Prevention and Research Institute of Texas grant RP130397 and NIH grants S10OD012304-01 and P30CA016672 . We acknowledge the High Resolution Electron Microscopy Facility ( NIH grant P30CA016672 ) at UT-MDACC for performing the TEM studies. We are also grateful to the Flow Cytometry and Cellular Imaging Core Facility (FCCICF) ( NCI grant P30CA16672 ) at UT-MDACC for advice and help in flow cytometry experiments. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = aug,
day = "10",
doi = "10.1016/j.celrep.2021.109510",
language = "English (US)",
volume = "36",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}