Podocyte Mitosis – A Catastrophe

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.

Glomerular parietal epithelial cells in kidney physiology, pathology, and repair

“…In addition, podocytes sometimes stain positive for proliferation markers like Ki67 or BrdU, but this indicates cell-cycle entry and not necessarily podocyte mitosis. During glomerular injury, podocytes certainly enter the S-phase of the cell cycle to undergo hypertrophy, whereas when being forced to override the G 2 /M check point of the cell cycle, they usually undergo an aberrant mitosis leading to podocyte detachment and death, that is, mitotic catastrophe [10,11]. Finally, studies on human renal biopsy material are consistent with the concept that it is the PEC overgrowth that accounts for epithelial hyperplasia in crescentic and collapsing glomerulopathies [30].…”

“…These observations suggest that PECs represent podocyte progenitors that are maintaining a modulated capacity to divide until they are in an undifferentiated state [10]. Although PECs exhibit a simple cytoskeleton and a high proliferative capacity, the highly specialized podocyte phenotype requires the acquisition of a complex cytoskeleton structure that would be disrupted to assemble the mitotic spindle, making it difficult to efficiently complete cytokinesis [10]. Consistently, in PECs, Notch activation triggers proliferation by promoting entry into the S-phase of the cell cycle and mitotic division ( Fig.…”

“…Consistently, SSeCKS null mice show hyperplasia of PECs in otherwise normal glomeruli and develop significantly worse proteinuric glomerular disease, marked by increased PEC proliferation and expression of nuclear cyclin D1 [9 & ]. These observations suggest that PECs represent podocyte progenitors that are maintaining a modulated capacity to divide until they are in an undifferentiated state [10]. Although PECs exhibit a simple cytoskeleton and a high proliferative capacity, the highly specialized podocyte phenotype requires the acquisition of a complex cytoskeleton structure that would be disrupted to assemble the mitotic spindle, making it difficult to efficiently complete cytokinesis [10].…”

Podocyte Number in Children and Adults

“…[48][49][50][51][52] After this point, podocytes are considered incapable of undergoing mitosis under normal conditions, although podocyte proliferation occurs in certain pathologic conditions, such as HIVassociated nephropathy. 53,54 Podocytes can be induced to proliferate in vitro when cultured from freshly isolated glomeruli, 55 but these cells express low levels of many of the podocyte-specific differentiation markers, suggesting that podocytes are only capable of proliferating after they have dedifferentiated to a certain degree. Recent evidence suggests that progenitor cells residing in the JGA 56 and Bowman's capsule (PECs) [57][58][59][60][61] may give rise to podocytes.…”

RETRACTION: STAT3 Regulates Steady-State Expression of Synaptopodin in Cultured Mouse Podocytes

“…One possibility is that Synpo normally plays a role to prevent STAT3 activation from causing podocytes to re-enter the cell cycle, a process that cannot occur without marked rearrangement of the cytoskeleton (Narumiya and Yasuda, 2006). On the other hand, the presence of actin-stabilizing factors such as Synpo could also contribute to the "mitotic catastrophe" that occurs when podocytes re-enter the cell cycle but fail to complete cytokinesis (Lasagni et al, 2013;Liapis et al, 2013). To our knowledge, there has not been any in vivo experiment in which Synpo expression is artificially elevated in podocytes.…”