Upregulation of histone deacetylase 1 decreased klotho transcription and promoted septic kidney injury in the rats

Septic acute kidney injury (AKI) is a severe complication commonly seen in critical patients with a complicated pathogenesis. Recent studies have shown that dysregulation of epigenetic control, particularly histone modification imbalance, plays a pivotal role in its development. Klotho is a transmembrane protein primarily expressed in renal distal tubules serving as a protective factor in maintaining renal homeostasis. In order to explore the role and mechanism of klotho in the AKI, male adult SD rats with LPS-induced AKI at 5mg/kg were studied. Serum concentrations of creatinine (51.0±5.0 vs 31.0±1.6,μmol/L) and BUN (20.3±8.0 vs 5.1±0.9) were increased but creatinine clearance (0.6±0.3 vs 1.1±0.1, ml/min) was decreased at 24h after LPS injections via tail veins (n=5/group, P< 0.05, t-test). They were not altered at 6h, and 12h. Compared with baseline (28.8±1.7, ng/ml), serum klotho declined in the rats at 12 (18.5±3.4) and 24h (19.6±3) but not 6h while serum cystatin C, kidney-injury-molecular-1 were not changed at all time points. Renal klotho protein abundances were lowered at 6 (66.8±6.4, % of vehicles, same as below), 12 (38±1.6) and 24-h (40.5±6.2) in LPS relative to vehicle rats. Klotho mRNA expressions were decreased at 6 (27.9±4.6), 12 (36.2±10.7) and 24-h (22.2±3.8). HDAC1 protein abundances were increased only at 6-h(150.6±11.8). HDAC1 mRNA expressions were promoted at 6 (190.8±53.4), 12 (203.1±52.1) and 24-h (228.2±22.3). Renal acetylation level of klotho was decreased (43.3±19.8) while the protein abundances of renal IL-6 (165.14±25.4), NGAL(104.9±20.1) and IGFBP7 (130.8±8.4) were elevated in 24h LPS group. In the cultured mouse distal convoluted tubule cells, the protein (57.8±1.5) and mRNA (66.4±13.3) of klotho were lower in LPS (10μg/ml for 24h) group than vehicle group with increased IL-6 production(255.8±38.3). HDAC1 protein (152.1±15.2) increased along with the nucleus activity of acetyltransferase (112.43±8.1, n=6, P< 0.05, t-test). HDAC1-specific inhibitor (pyroxamide,5μmol,24h) restored the klotho protein abundance and alleviated the IL-6 production caused by LPS treatment (n=5-6, P< 0.05, one-way ANOVA, Holm-Sidak test). Our results suggest that HDAC1 may inhibit klotho transcription through aberrant deacetylation, serving as an epigenetic link between systemic inflammation and kidney injury in sepsis. Targeted intervention in the HDAC1/klotho axis holds a promise for the prevention and treatment of septic AKI. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.