Abstract
Growing evidence has shown that podocyte number is a critical determinant for the development of glomerulosclerosis and progressive renal failure. We previously reported that mitochondrial dysfunction (MtD) is an early event in podocyte injury. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is an important modulator of mitochondrial biogenesis. Here, we investigated the role of PGC-1α overexpression in podocyte depletion and the involvement of mitochondria in this process. Following chronic aldosterone (Aldo) infusion for 14 days, we observed a remarkable podocyte loss, podocyte phenotypic changes, and albuminuria in WT mice. However, all these abnormalities were significantly attenuated in PGC-1α transgenic mice. Next, we examined mitochondrial function in both genotypes with or without Aldo infusion. As expected, Aldo-induced MtD in glomeruli was markedly improved in PGC-1α transgenic mice. In vitro, Aldo induced podocyte detachment and phenotypic changes in line with MtD in dose- and time-dependent manners. Similarly, ethidium bromide, an inducer of MtD, mimicked Aldo effects on podocyte detachment and phenotypic alterations. Notably, overexpression of PGC-1α in podocytes entirely reversed Aldo-induced podocyte detachment, phenotypic changes, and MtD. Taken together, these findings demonstrate that PGC-1α protects against podocyte depletion and phenotypic changes possibly by maintaining normal mitochondrial function.
Highlights
Podocytes are highly differentiated glomerular epithelial cells with limited potential to divide
PGC-1α transgenic www.impactjournals.com/oncotarget mice exhibited improved albuminuria (Figure 2D), while the kidney function evidenced by Blood urea nitrogen (BUN), blood creatinine and creatinine clearance displayed no difference between genotypes with or without Aldo treatment (Figure 2E2G)
Podocyte depletion occurs in many glomerular diseases, including focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, immunoglobulin A nephropathy and lupus nephritis [18]
Summary
Podocytes are highly differentiated glomerular epithelial cells with limited potential to divide. They are primarily responsible for maintaining the integrity of the glomerular basement membrane, and abnormal podocyte morphology and dysfunction are involved in proteinuria [1]. Mitochondria are complex intracellular organelles that are responsible for various metabolic functions, including energy production via oxidative phosphorylation. Mitochondria are a major source of reactive oxygen species (ROS), and the overproduction of ROS damages mitochondrial DNA (mtDNA) and the oxidation respiratory chain, which causes mitochondrial dysfunction (MtD) [4]. MtD is characterized by increased ROS production, the accumulation of impaired mtDNA, and progressive respiratory chain dysfunction [5,6,7]. The role of MtD in podocyte loss remains unknown
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