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such as nephrin, and a reorganization of actin cytoskeleton. It was observed
that formation of dot-like actin-rich structures were enhanced by rapamycin,
and this actin reorganization was caused by a loss of Nck (non-catalytic region
of tyrosine kinase adaptor protein 1), which is an actin regulating protein and
a cytoskeleton adaptor that links nephrin to actin cytoskeleton (
Vollenbroker
et al., 2009
). Besides long-term rapamycin treatment, diabetes also leads to
malfunction of blood-urine filtration barrier, resulting in proteinuria. It was
demonstrated that diabetes led to overactivation of mTOR signaling in dam-
aged podocytes in diabetic mice, leading to mislocalization of slit diaphragm
protein nephrin and also TJ adaptor ZO-1, moving from plasma membrane
to cytosol (
Inoki et al., 2011
). The fact that the phenotypes of podocyte dam-
ages found in diabetic animals mimicked podocyte-specific TSC1 knockout
mice (note: TSC1 is the mTORC1 upstream negative regulator, see
Fig. 6.3
),
illustrating the involvement of mTORC1 signaling in the podocyte-based fil-
tration barrier.The role of mTORC1 and mTORC2 in regulating the blood-
urine filtration barrier was also illustrated in a study using podocyte-specific
raptor or rictor knockout mice (
Godel et al., 2011
). Mice lacking mTORC1
in podocytes as the result of podocyte-specific raptor knockout developed
significant albuminuria, a form of proteinuria. In contrast, loss of mTORC1
in podocytes of adult mice triggered by conditional knockout of raptor only
had a mild effect and the level of protein excreted in urine in these mice was
insignificantly higher than that of the wild-type (
Godel et al., 2011
). Addition-
ally, it was shown that when conditional knockout of raptor was performed in
mice with genetic background that was known to be more sensitive toward
podocyte damage, significant proteinuria was induced (
Godel et al., 2011
).
Taken together, these findings illustrate that mTORC1 signaling is required
for proper development of podocytes to form the blood-urine filtration bar-
rier; whereas in adult mice after podocytes are developed and the blood-urine
filtration barrier is fully functional, mTORC1 is necessary for maintenance of
podocyte functions, and mTORC1 is more important in animals with specific
genetic background. It is noted that while podocytes are needed mTORC1
to maintain the filtration barrier function, overactivation of mTORC1 sig-
naling in podocytes also leads to a disruption of the barrier. This indicates
that a precise control on the availability of mTORC1 is needed to maintain
the homeostasis of the barrier function. Regarding the role of mTORC2 in
podocyte-mediated barrier function, it was shown that in podocyte-specific
rictor knockout mice, only transient albuminuria was found when these mice
were challenged by a BSA overload (
Godel et al., 2011
). However, when rap-
tor and rictor were simultaneously knockout in podocytes, massive proteinuria
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