Sirtuin1 maintains actin cytoskeleton by deacetylation of cortactin in injured podocytes

Recent studies have highlighted the renoprotective effect of sirtuin1 (SIRT1), a deacetylase that contributes to cellular regulation.However, thepathophysiologic roleofSIRT1inpodocytes remains unclear.Here,weinvestigated the function of SIRT1 in podocytes. We first established podocyte-specific Sirt1 knockout (SIRT1^pod-/-) mice.We then induced glomerular disease by nephrotoxic serum injection. The increase in urinary albumin excretion andBUN and theseverity ofglomerular injurywere all significantly greater inSIRT1^pod-/-mice than inwild-typemice.Western blot analysis and immunofluorescence showed a significant decrease in podocyte-specific proteins in SIRT1^pod-/- mice, and electron microscopy showed marked exacerbation of podocyte injury, including actin cytoskeleton derangement in SIRT1^pod-/-mice comparedwithwild-typemice. Protamine sulfate-induced podocyte injury was also exacerbated by podocyte-specific SIRT1 deficiency. In vitro, actin cytoskeleton derangement in H₂O₂-treated podocytes became prominent when the cells were pretreated with SIRT1 inhibitors. Conversely, this H₂O₂-induced derangement was ameliorated by SIRT1 activation. Furthermore, SIRT1 activation deacetylated the actin-binding and-polymerizing protein cortactin in the nucleus andfacilitated deacetylated cortactinlocalizationinthecytoplasm. Cortactin knockdown or inhibition of the nuclear export of cortactin induced actin cytoskeleton derangement and dissociation of cortactin fromF-actin, suggesting the necessity of cytoplasmic cortactin formaintenance of the actin cytoskeleton. Taken together, these findings indicate that SIRT1 protects podocytes and prevents glomerular injury by deacetylating cortactin and thereby, maintaining actin cytoskeleton integrity.