ERRγ deletion in podocytes accelerates aging related kidney disease.

We have recently demonstrated that treatment of aged mice with a pan-ERR agonist reverses age-related increase in urinary albumin, decrease in podocyte density, impaired mitochondrial function, and inflammation. The contribution of individual isoforms of ERRs however has not been determined. Since the aging kidney showed a possible compensatory increased expression of ERRγ in the podocytes, in the face of decreased ERRα expression, in the present study we aimed to determine the role of ERRγ in aging podocyte. To this end, we cross bred ERRγ floxed mice with podocin-Cre mice to achieve a podocyte-specific ERRγ deletion. While these mice at 3 months of age showed no effect on albuminuria compared to the wild type, when the mice were aged to 21 months of age, there was a significant increase in albuminuria and decrease in podocyte density. Furthermore, we found that the podocyte deletion of ERRγ primarily targeted the expression of mitochondrial biogenesis regulator PGC-1α, and mitochondrial fatty acid oxidation enzymes CPT1a and MCAD in the kidney. Electron Microscopy (EM) revealed thickened glomerular basement membrane and diffuse podocyte foot process effacement, as well as severe mitochondrial damage including cristae abnormalities, fragmentation, and changes indicative of altered fusion and fission dynamics. Fluorescence Lifetime Imaging Microscopy (FLIM) to determine NADH and FAD lifetimes indicate a metabolic shift from mitochondrial oxidative phosphorylation towards glycolysis, and decrease in mitochondrial redox capacity. Considering a significantly decreased expression of ERRα in aging podocytes plus its traditional role in mitochondrial function, these studies using podocyte ERRγ deletion suggested an overlapping mechanism for ERRα/ERRγ to act as modulators of age-related mitochondrial dysfunction and age-related kidney disease.