Histone deacetylase 3‑mediated histone deacetylation combined with activating transcription factor 3 promotes renal fibrosis by inhibiting Klotho.

Renal fibrosis is a representative pathological trait of renal aging and chronic kidney disease. However, the regulatory mechanisms of histone deacetylation in renal fibrosis remain unclear. A mouse renal fibrosis model was constructed using the unilateral ureteric obstruction method, and HK2 cells treated with TGF‑β were used to create a renal fibrosis cell model. Low expression of Klotho in renal fibrosis is associated with histone deacetylase 3 (HDAC3)‑mediated histone deacetylation. After TGF‑β treatment, H3K9ac and Klotho binding was markedly decreased, while H3K9ac was enriched in the Klotho group after the addition of the HDAC3 inhibitor. Further experiments demonstrated that HDAC3 binding activates transcription factor 3, inhibits Klotho transcription and promotes cellular renal fibrosis. The absence of Klotho may activate the Wnt/β‑catenin and NF‑κB pathways to promote oxidative stress and inflammation, thereby exacerbating the fibrotic process. HDAC3 binds to ATF3 to transcriptionally repress Klotho, leading to activation of the Wnt/β‑catenin and NF‑κB pathways and exacerbation of renal fibrosis.