PGC1α is Required for the Renoprotective Effect of LncRNA Tug1 <i>in vivo</i> and Links Tug1 with Urea Cycle Metabolites

Abstract

Long non-coding RNA Tug1 is emerging as a novel therapeutic target in the progression of diabetic nephropathy (DN), but the molecular basis of its protection in vivo remains poorly understood. Here we generated a triple mutant diabetic mouse model coupled with metabolomic profiling data to interrogate whether Tug1 interaction with PGC1α is required for the mitochondrial remodeling and progression of DN in vivo . Using an established diabetic mouse model with conditional inducible deletion of Pgc1α in podocytes, alone ( db/db;Pgc1α Pod-f/f ), or in combination with podocyte-specific Tug1 overexpression ( db/db;TugPodTg ; Pgc1αPod-f/f ), we found that the protective phenotype of Tug1 overexpression in diabetic db/db mice was reversed with conditional knockout of Pgc1α in podocytes, suggesting the requirement of PGC1α for the modulatory effects of lncRNA Tug1 in DN progression. Mechanistically, our findings highlight the multifaceted contributions of lncRNA Tug1 on mitochondrial bioenergetics, biogenesis and dynamics in podocytes of diabetic mice. Using an unbiased metabolomics profiling, we unexpectedly discovered that altered urea cycle metabolites and mitochondrial arginase 2 play an important role in Tug1/PGC1α-induced mitochondrial remodeling. Our work identifies an important but previously unappreciated functional role of lncRNA Tug1/PGC1α axis on mitochondrial metabolic homeostasis and urea cycle metabolites in experimental models of diabetes.