The podocyte resembles the most vulnerable component of the glomerulus, and insults that compromise the function of this specialized epithelial cell are Abiraterone associated with proteinuria and renal failure. The selective mTORC1 inhibitor rapamycin can cause proteinuria in both humans and animal models of kidney disease, but also has been shown to ameliorate glomerular disease, suggesting a pivotal and incompletely understood role in podocyte homeostasis. The genetic dissection of mTOR function provides the tools to dissect the opposing effects of mTOR activity on the integrity of the glomerular filter and the progression of podocyte disease, providing a molecular framework to correctly utilize mTOR inhibitors in the treatment of progressive glomerulopathies. Role of mTOR signaling for glomerular development and maintenance.

Inhibition of mTORC1 has frequently been reported to cause proteinuria in patients (15). Rapamycin increases the risk for proteinuria in chronic allograft nephropathy (17) and is associated with increased podocyte apoptosis and development of focal segmental glomerulosclerosis (FSGS) after renal transplantation (16, 17). Utilizing podocyte-specific mTOR-deficient mice, our data document that mTOR function in podocytes is essential for the integrity of the filtration barrier. Loss of mTORC1 results in progressive glomerulosclerosis; this is further aggravated by the additional deletion of mTORC2, uncovering an unknown role for mTORC2 in podocyte homeostasis. Strikingly, the mTORC1 loss-of-function phenotype is similar to the phenotype observed in podocyte-specific insulin receptor�Cdeficient mice (37).

Together these data underline the importance of the growth hormone receptor PI3K-mTORC1 axis for podocyte biology. Intriguingly, podocytes seem to be particularly sensitive to mTORC1 deletion during glomerular development, indicating that mTORC1 is of particular importance during podocyte growth and adaptation. mTORC1 regulates cell growth by maintaining the appropriate balance between anabolic processes, such as macromolecular Brefeldin_A synthesis and nutrient storage, and catabolic processes, such as autophagy and the utilization of energy stores. With the transition to the capillary loop state, the maturing podocytes lose their capability of cell replication. Thus, podocytes can only increase their size to compensate for further glomerular expansion during glomerular development. Podocytes need to cover the surface of the glomerular basement membrane (GBM); after the terminal differentiation of podocytes, any further increase in filtration area will require a compensatory cell growth of podocytes. Our data suggest that activation of mTORC1 allows the podocyte to participate in glomerular expansions during kidney development.