The deacetylase sirtuin 6 protects against kidney fibrosis by epigenetically blocking β-catenin target gene expression

The Role of Sirtuins in Kidney Diseases

“…SIRT6 also functions as a corepressor of HIF-1α, suppressing glucose uptake and glycolysis [ 70 ]. In the kidney, SIRT6 plays an important role in podocyte injury and renal fibrosis in podocytes and proximal epithelial tubular cells [ 72 , 73 , 74 ].…”

“…Honokiol, a pharmaceutical SIRT3 activator, decreased renal inflammation and fibrosis through regulation of mitochondrial dynamics via the NF-κB/TGF-β1/Smad signaling pathway [ 152 ]. SIRT6 knockout aggravated TGF-β-induced fibrosis in mouse tubular epithelial cells, while pharmacological inhibition of SIRT6 deacetylase activity by OSS_128167 induced kidney fibrosis in a mouse model of UUO through modulation of the Wnt/β-catenin signaling pathway [ 74 ]. Therefore, various sirtuins appear to be involved in kidney fibrosis and related processes.…”

Sirtuin 6 and renal injury: another link in the β-catenin chain?

“…4 The isoform Sirt6 is, like Sirt1, predominantly in the nucleus, and was recently shown to be protective in acute kidney injury by reducing extracellularsignal-regulated kinase-1/2 activity. 5 However, the role of Sirt6 in CKD is not well known and is the topic of investigation by Cai et al 6 in this issue of Kidney International. The authors show that Sirt6 expression is upregulated in renal tubules in the unilateral ureteral obstruction model and 2 weeks after unilateral ischemia/reperfusion injury.…”

“…Both pharmacologic inhibition of Sirt6 in vivo and genetic knock-down in vitro with short hairpin RNA leads to increased fibrosis and a profibrotic epithelial phenotype, respectively. 6 The chemical inhibitor that was used may also suppress Sirt1, albeit to a lesser extent than Sirt6, so genetic tools are important for verifying these results.…”

“…This pathway has been implicated in CKD, predominantly due to signaling within the fibroblast/pericyte population, which leads to myofibroblast activation and extracellular matrix production. 7 Cai et al 6 Although questions remain regarding the stimulus that leads to Sirt6 activity and other potential transcriptional targets that may be altered by nuclear Sirt6/b-catenin interactions, the article by Cai et al 6 adds to our preclinical understanding of antifibrotic pathways in CKD. The possibility that other Sirt6 targets (e.g., TGF-b/Smads) also play a role in its antifibrotic effects has not been completely ruled out.…”