Sirt6 ameliorates high glucose-induced podocyte cytoskeleton remodeling via the PI3K/AKT signaling pathway
Background: Podocyte injury is a critical factor in the development and progression of diabetic kidney disease (DKD), contributing to the onset of albuminuria. Cytoskeletal remodeling is an early indicator of podocyte damage in DKD, though the mechanisms behind this process remain unclear. Histone deacetylase Sirtuin6 (Sirt6) has been identified as a key player in the progression of DKD, and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) pathway is known to regulate podocyte cytoskeletal integrity. However, the interplay between Sirt6, the PI3K/AKT pathway, and DKD progression is yet to be fully understood.
Methods: Renal injury in db/db mice was assessed using PAS staining and transmission electron microscopy. The expression of Sirt6 in the glomeruli of db/db mice was evaluated by immunofluorescence. The effects of Sirt6 activation were studied using UBCS039, a Sirt6 activator, in diabetic mouse kidneys. To manipulate Sirt6 expression in podocytes, we used the Sirt6 inhibitor OSS_128167 to downregulate Sirt6 and a recombinant plasmid to induce its upregulation. High glucose (HG)-induced podocyte damage was assessed in vitro by observing cytoskeletal changes with phalloidin staining, measuring podocyte apoptosis via flow cytometry, and evaluating PI3K/AKT signaling activation by Western blot.
Results: In db/db mice, renal damage was observed, including increased albumin-to-creatinine ratio (ACR), expanded mesangial matrix, fused podocyte foot processes, and thickened glomerular basement membrane. Expression of Sirt6 and PI3K/AKT pathway components was reduced in these mice. Treatment with UBCS039 led to increased expression of Sirt6 and components of the PI3K/AKT pathway, which helped alleviate renal damage. In vitro, HG exposure induced consistent Sirt6 expression in podocytes. Activation of the PI3K/AKT pathway via Sirt6 overexpression improved podocyte cytoskeletal remodeling and reduced apoptosis in HG-treated immortalized human podocytes. Conversely, Sirt6 inhibition by OSS_128167 exacerbated HG-induced podocyte damage.
Conclusions: Sirt6 protects podocytes from HG-induced cytoskeletal remodeling and apoptosis by activating the PI3K/AKT signaling pathway. These results suggest that Sirt6 activation may be a promising therapeutic approach for addressing podocyte injury in DKD.