The Role of Peroxisome Proliferator-Activated Receptor γ Coactivator 1α (PGC-1α) in Kidney Disease

Abstract

Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a key transcriptional regulator of mitochondrial biogenesis and function. Several recent studies have evaluated the role of PGC-1α in various renal cell types in healthy and disease conditions. Renal tubule cells mostly depend on mitochondrial fatty acid oxidation for energy generation. A decrease in PGC-1α expression and fatty acid oxidation is commonly observed in patient samples and mouse models with acute and chronic kidney disease. Conversely, increasing PGC-1α expression in renal tubule cells restores energy deficit and has been shown to protect from acute and chronic kidney disease. Other kidney cells, such as podocytes and endothelial cells, are less metabolically active and have a narrow PGC-1α tolerance. Increasing PGC-1α levels in podocytes induces podocyte proliferation and collapsing glomerulopathy development, while increasing PGC1-α in endothelial cells alters endothelial function and causes microangiopathy, thus highlighting the cell-type-specific role of PGC-1α in different kidney cells.

Keywords: Notch; PGC-1α; mitochondria; podocyte; tubular cells.

Figure 1. Biological function of PGC-1α

PGC-1α co-activates transcription factors such as estrogen-related receptors (ERRs), Retinoid X receptors (RXRs), peroxisome proliferator-activated receptors (PPARs), Mitochondrial transcription factor A (Tfam), and nuclear respiratory factors (NRFs), known to regulate different aspects of energy metabolism including angiogenesis, fatty acid oxidation, antioxidant, and mitochondrial biogenesis.

Figure 2. Energetic alterations in renal tubule epithelial cells and renal fibrosis

Renal tubule epithelial cell use fatty acids to produce ATP. Kidney injury directly induces mitochondrial damage and suppresses PGC-1α expression, hence blocking PPARα activity, mitochondrial biosynthesis and NAD synthesis. All these changes lead to fatty acid oxidation failure. Defective fatty acid oxidation results in lipid accumulation, tubule epithelial cell dedifferentiation, and apoptosis.

Figure 3. Potential contributions of excessive PGC-1α to the development of collapsing glomerulopathy

Podocytes use glucose as energy fuel. In certain circumstances, drug-induced and other mitochondrial injuries cause podocyte ATP deficiency. PGC-1α is therefore upregulated to compensate depleted cell energy, but podocytes have a narrow PGC-1α tolerance. Excessive PGC-1α changes podocyte mitochondrial intrinsic properties and cell fate, leading to collapsing glomerulopathy.