Cell cycle regulatory proteins in podocyte health and disease

Abstract

The glomerular visceral epithelial cell, or podocyte, is a highly specialized and terminally differentiated cell that is fundamental to the integrity of the glomerular filtration barrier and functions to prevent urinary protein leakage and to oppose intracapillary hydrostatic pressure. Common to many human kidney diseases and experimental animal models is a strong association between podocyte injury and the development of progressive kidney disease. Studies have shown that a decline in podocyte number strongly correlates with, and likely underlies, proteinuria and the progression to glomerulosclerosis. Maintenance of podocyte differentiation, essential to its normal structure and function, is challenged in the setting of glomerular injury, with very divergent outcomes dependent upon the inciting injury. In response to injury, podocytes may undergo several cell fates, including proliferation, de-differentiation, hypertrophy, apoptosis, or necrosis. Common to these potential outcomes of renal injury is their ultimate regulation at the level of the cell cycle. Positive regulators (cyclins and cyclin-dependent kinases) and negative regulators (cyclin-dependent kinase inhibitors) coordinate the cell cycle. There is now a large body of literature confirming the importance of cell cycle regulatory proteins in the cellular response to injury. Emerging lessons from mouse knockout experiments highlight that the cell cycle machinery operates differently in distinct cell types. Recent studies focusing on the roles of cell cycle regulatory proteins specifically in podocytes have provided important clues on how these proteins operate to constrain cell proliferation and preserve differentiation in health, and how they modulate the dysregulated phenotype in diseased states. In disease, both a failure to regenerate lost podocytes and an inappropriate proliferative response can have profound consequences for glomerular structure and function. Here, we will review the latest advances in understanding the roles of cell cycle regulatory proteins in diseases of the podocyte.