SIRT6 mitigates acute kidney injury by enhancing lipid metabolism and reducing tubular epithelial cell apoptosis via suppression of the ACMSD signaling pathway

Abstract

Acute kidney injury (AKI) remains a critical condition with substantial morbidity and mortality in hospitalized patients. Emerging research has underscored the protective role of SIRT6 in kidney diseases through diverse signaling pathways. Our current report aimed to elucidate the mechanisms by which SIRT6 mitigated the progression of AKI. Immunohistochemical and Oil Red O staining techniques were employed to assess the expression of SIRT6 and lipid metabolism in both AKI patients and AKI mice treated with UBCS039, a specific SIRT6 activator (30 mg/kg, i.p.). Kidney tissues from AKI mice were analyzed using LC-MS/MS to uncover SIRT6-related signaling pathways involved in AKI. Additionally, human proximal renal tubule cells (HK−2) were exposed to UBCS039 or transfected pcDNA3.1-SIRT6 overexpression plasmid to investigate the underlying signaling mechanisms of SIRT6 on lipid metabolism using Western blotting analysis and Oil Red O staining. Gene expression levels of ACMSD was detected by qRT-PCR and Western blotting in HK-2 cells. Dual-luciferase reporter assay was used to verify the effect of SIRT6 on regulating ACMSD transcription. Our findings revealed a significant reduction in SIRT6 expression in both AKI patients and AKI mice. Treatment with UBCS039, however, significantly decreased lipid accumulation and apoptosis in AKI mice. Proteomic analysis and Dual-luciferase reporter assay identified ACMSD as a downstream target of SIRT6. In vitro studies further demonstrated that SIRT6 enhanced lipid metabolism and mitigated apoptosis through the inhibition of ACMSD expression. This study demonstrated that SIRT6 promoted lipid metabolism by inhibiting the ACMSD pathway, thereby reducing apoptosis in AKI. These findings suggested that targeting ACMSD could offer a novel therapeutic strategy for SIRT6-mediated intervention in AKI.