Pgc1 Alpha Is Required For The Renoprotective Effect Of Lncrna Tug1 In Vivo And Links Tug1 With Urea Cycle Metabolites

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 1 alpha (PGC1 alpha) is required for mitochondrial remodeling and progression of DN in vivo. We find that, compared with diabetic conditional deletion of Pgc1 alpha in podocytes alone (db/db; Pgc1 alpha(Pod-f/f)), diabetic Pgc1 alpha knockout combined with podocyte-specific Tug1 overexpression (db/db; Tug(PodTg); Pgc1 alpha(Pod-f/f)) reverses the protective phenotype of Tug1 overexpression, suggesting that PGC1 alpha 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/PGC1 alpha-induced mitochondrial remodeling. Our work identifies a functional role of the Tug1/PGC1 alpha axis on mitochondrial metabolic homeostasis and urea cycle metabolites in experimental models of diabetes.