ATF4-mediated endoplasmic reticulum stress drives tubular epithelial cell senescence in rhabdomyolysis-induced acute kidney injury

Rhabdomyolysis-induced acute kidney injury (RM-AKI) is a life-threatening complication with incompletely understood pathogenesis. Recent studies have highlighted the roles of endoplasmic reticulum stress (ERS) and cellular senescence in kidney diseases; however, their involvement in RM-AKI remains unclear. A mouse model of glycerol-induced RM-AKI was established, and kidney injury was assessed at 48 h, 7 days, 14 days, and 28 days. Techniques including transcriptomic sequencing, quantitative PCR, Western blotting, immunofluorescence, SA-β-galactosidase staining, and transmission electron microscopy were employed to detect markers of ERS and cellular senescence at different timepoints. In vitro experiments involved treating HK-2 cells with myoglobin to simulate tubular injury, and siRNA was used to knockdown ATF4 to investigate its molecular mechanisms. Early and sustained activation of ERS accompanied by tubular epithelial cell senescence was observed during RM-AKI. Transcriptomic analysis revealed early enrichment of ERS and senescence-related signaling pathways. The ERS markers GRP78, CHOP, and ATF4, as well as the senescence marker p21, were significantly upregulated. Transmission electron microscopy showed endoplasmic reticulum dilation and mitochondrial swelling, while SA-β-gal staining indicated an increased proportion of senescent cells. In vitro, myoglobin induced ERS and cellular senescence in HK-2 cells, both of which were markedly attenuated by ATF4 knockdown. This study provides the first evidence that ATF4-mediated ERS drives the senescence of renal tubular epithelial cells in RM-AKI. This new finding, identifying ATF4 as a key upstream regulator linking ERS to cellular senescence in this pathological state, reveals a previously unrecognized pathogenic mechanism. Targeting ATF4 and its downstream ERS signaling pathways may represent a promising therapeutic strategy for treating RM-AKI.