SIRT3 deficiency aggravates renal injury and fibrosis in chronic kidney disease and is associated with intestinal barrier dysfunction and gut microbiota dysbiosis.

BACKGROUND

Chronic kidney disease (CKD) is a progressive disorder characterized by persistent renal dysfunction, inflammation, and fibrosis. Sirtuin 3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase, has been implicated in the regulation of mitochondrial homeostasis, oxidative stress, and renal injury. However, whether SIRT3 participates in CKD progression through gut-kidney axis-related alterations remains unclear. This study investigated the role of SIRT3 in renal injury, fibrosis, intestinal barrier dysfunction, and gut microbiota dysbiosis in CKD.

METHODS

An adenine-induced CKD model was established in global SIRT3 knockout mice. Renal function, inflammatory markers, histopathological injury, fibrosis-related proteins, colonic injury, intestinal barrier-related proteins, and gut microbial composition were evaluated. In parallel, human proximal tubular epithelial HK-2 cells were treated with transforming growth factor-β1 (TGF-β1), with or without the SIRT3 inhibitor 3-TYP, to assess profibrotic responses and apoptosis in vitro. Gut microbiota alterations were analyzed by 16S rRNA gene sequencing.

RESULTS

SIRT3 deficiency alone did not produce overt abnormalities under basal conditions, but significantly aggravated adenine-induced renal dysfunction, inflammatory responses, tubulointerstitial fibrosis, and structural kidney injury. In CKD mice, SIRT3 deficiency also worsened colonic injury, reduced the expression of zonula occludens-1 and occludin, and was associated with more pronounced gut microbiota dysbiosis. In vitro, inhibition of SIRT3 further enhanced TGF-β1-induced profibrotic protein expression and apoptosis in HK-2 cells. Correlation analysis further suggested significant associations between specific microbial taxa and indices of renal fibrosis and renal dysfunction.

DISCUSSION: These findings indicate that SIRT3 exerts a protective role in CKD progression. Loss of SIRT3 aggravates CKD progression not only by worsening local renal injury, but also in association with gut-kidney axis-related abnormalities. Collectively, our results suggest that SIRT3 may represent a potential therapeutic target for CKD and provide a basis for further mechanistic investigation of its role in renal fibrosis and gut-kidney axis dysfunction.