Title:Podocyte Mitosis – A Catastrophe
Volume: 13
Issue: 1
Author(s): L. Lasagni, E. Lazzeri, S. J. Shankland, H.-J. Anders and P. Romagnani
Affiliation:
Keywords:
Actin cytoskeleton, foot process, glomerulosclerosis, mitotic catastrophe, podocyte, renal progenitor
Abstract: Podocyte loss plays a key role in the progression of glomerular disorders towards
glomerulosclerosis and chronic kidney disease. Podocytes form unique cytoplasmic extensions, foot
processes, which attach to the outer surface of the glomerular basement membrane and interdigitate with
neighboring podocytes to form the slit diaphragm. Maintaining these sophisticated structural elements requires
an intricate actin cytoskeleton. Genetic, mechanic, and immunologic or toxic forms of podocyte injury can
cause podocyte loss, which causes glomerular filtration barrier dysfunction, leading to proteinuria. Cell
migration and cell division are two processes that require a rearrangement of the actin cytoskeleton; this
rearrangement would disrupt the podocyte foot processes, therefore, podocytes have a limited capacity to
divide or migrate. Indeed, all cells need to rearrange their actin cytoskeleton to assemble a correct mitotic
spindle and to complete mitosis. Podocytes, even when being forced to bypass cell cycle checkpoints to initiate
DNA synthesis and chromosome segregation, cannot complete cytokinesis efficiently and thus usually
generate aneuploid podocytes. Such aneuploid podocytes rapidly detach and die, a process referred to as
mitotic catastrophe. Thus, detached or dead podocytes cannot be adequately replaced by the proliferation of
adjacent podocytes. However, even glomerular disorders with severe podocyte injury can undergo regression
and remission, suggesting alternative mechanisms to compensate for podocyte loss, such as podocyte
hypertrophy or podocyte regeneration from resident renal progenitor cells. Together, mitosis of the terminally
differentiated podocyte rather accelerates podocyte loss and therefore glomerulosclerosis. Finding ways to
enhance podocyte regeneration from other sources remains a challenge goal to improve the treatment of
chronic kidney disease in the future.
