SIRT1 is an NAD-dependent deacetylase. One important role of SIRT1 is
its deacetylation activity in the modulation of cell stress signals via epigenetics. In
podocytes, SIRT1 regulates the expression of important genes such as PGC-1α,
Foxo4, p65 and STAT3, which act to maintain podocyte function by modulating the
levels of histone acetylation.
Here, we confirmed that SIRT1 protects podocytes by maintaining PGC-1α via its
deacetylase-activated transcriptional activity in mitochondria and podocytes. We then showed that the alteration of Foxo4
(forkhead box O4) acetylation and decrease in SIRT1 promote podocyte apoptosis in diabetic nephropathy, resulting in
the gradual development of diabetic nephropathy.
Next, we showed that advanced glycation end products (AGEs) induced p65 and STAT3 acetylation in human podocytes.
Decreased Sirt1 activity in podocytes results in the development of proteinuria and kidney injury via the acetylation of
p65 and STAT3. These findings suggest that the beneficial effects of SIRT1 in diabetic nephropathy act via the
deacetylation of transcription factors.
In addition to its essential role in regulating the epigenetics of podocytes, we recently showed that SIRT1 is necessary to
maintaining the function of slit membranes and podocytes. The actin cytoskeleton becomes vulnerable to various stresses,
including oxidative stress, which in turn leads to the derangement and effacement of foot processes, slit membrane
dysfunction, and proteinuria. SIRT1 protects podocytes and prevents glomerular injury by deacetylating cortactin and
changing cortactin localization, thereby maintaining the integrity of the actin cytoskeleton.
We expect that SIRT1 will be shown to sufficiently suppress the development of kidney dysfunction and will be proven
useful in the near future. The clinical application of SIRT1-activated chemical agents has just started, and results are