PGC-1α in Disease: Recent Renal Insights into a Versatile Metabolic Regulator

Abstract

Peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α) is perhaps best known as a master regulator of mitochondrial biogenesis and function. However, by virtue of its interactions as a coactivator for numerous nuclear receptors and transcription factors, PGC-1α also regulates many tissue-specific tasks that include adipogenesis, angiogenesis, gluconeogenesis, heme biosynthesis, thermogenesis, and cellular protection against degeneration. Knowledge about these functions continue to be discovered with ongoing research. Unsurprisingly, alterations in PGC-1α expression lead to a range of deleterious outcomes. In this review, we provide a brief background on the PGC-1 family with an overview of PGC-1α's roles as an adaptive link to meet cellular needs and its pathological consequences in several organ contexts. Among the latter, kidney health is especially reliant on PGC-1α. Thus, we discuss here at length how changes in PGC-1α function impact the states of renal cancer, acute kidney injury (AKI) and chronic kidney disease (CKD), as well as emerging data that illuminate pivotal roles for PGC-1α during renal development. We survey a new intriguing association of PGC-1α function with ciliogenesis and polycystic kidney disease (PKD), where recent animal studies revealed that embryonic renal cyst formation can occur in the context of PGC-1α deficiency. Finally, we explore future prospects for PGC-1α research and therapeutic implications for this multifaceted coactivator.

Keywords: AKI; CKD; PGC-1α, disease; PKD; cancer; cilia; cystogenesis; kidney; nephron.

Figure 1

Systems affected and corresponding disease states in peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α) contexts. Schematic depicting the role of PGC-1α in select cellular processes including glucose uptake and disposal via glucose transporter 4 (GLUT4) in skeletal muscle (top, left), central nervous system reactive oxygen species (ROS) protection via PGC-1α uncoupling protein-2 (UCP2) (top, right), gluconeogenesis in the human liver (bottom, left), and insulin secretion from a pancreatic B-cell (bottom, right). Table summarizes key disease states and the associated organ systems in addition to the role PGC-1α plays in those organs and some of the genetic interactions with PGC-1α.

Figure 2

Kidney disease states associated with PGC-1α expression. Renal diagram illustrating general (top, left) and nephron compartment-specific functions of PGC-1α in addition to areas of future research. Kidney (left, maroon), nephron (right), glomerulus (orange), proximal tubule (green), and distal tubule (dark blue). References for cited studies listed within. (PT = proximal tubule, AKI = acute kidney injury).