Fine particulate matter (PM2.5) deposition in the lungs can induce pulmonary injury. Histone deacetylase 6 (HDAC6), a critical member of the histone deacetylase family, plays a key role in regulating lung diseases. In this study, we explored the mechanism of HDAC6 in PM2.5 (10 mg/kg)–induced pulmonary injury using an HDAC6 knockout (KO) mouse model, employing immunohistochemical, western blot, and transcriptome analyses. Results indicated that HDAC6 KO exacerbated PM2.5-induced epithelial barrier dysfunction by altering the expression of zonula occludens-1 (ZO-1) and zonula occludens-2 (ZO-2). Moreover, HDAC6 KO increased the susceptibility of lung tissue to PM2.5 by inhibiting E-cadherin expression and promoting N-cadherin expression. Transcriptome analysis of PM2.5-treated lungs in the HDAC6 KO group revealed significant alterations in the renin-angiotensin system (RAS). The expression levels of RAS components, including angiotensin-converting enzyme II (ACE2), angiotensin II (Ang II), renin, and Agtrl1b, were quantified. Notably, both PM2.5 and HDAC6 KO disrupted RAS balance. The PM2.5-treated HDAC6 KO group exhibited a pronounced reduction in ACE2 and elevation in Ang II, suggesting increased susceptibility to PM2.5. These results indicate that HDAC6 KO exacerbates PM2.5-induced pulmonary injury by affecting RAS balance. This study provides a theoretical foundation for understanding the role of HDAC6 in PM2.5-induced pulmonary injury.
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