肾脏疾病,包括慢性肾脏病(CKD)和急性肾损伤(AKI),与炎症有关。在这些肾损伤中调节炎症的机制仍不清楚。这里,我们证明了p300/CBP相关因子(PCAF),组蛋白乙酰转移酶,在db/db小鼠和脂多糖(LPS)注射小鼠的肾脏中过表达。此外,组蛋白乙酰化升高,比如H3K18ac,和一些炎症基因的上调,如ICAM-1,VCAM-1和MCP-1,在这些肾损伤中发现。此外,增加的H3K18ac被募集到LPS注射小鼠肾脏中ICAM-1,VCAM-1和MCP-1的启动子。体外研究表明,人肾近曲小管上皮细胞(HK-2)中PCAF敲低导致炎症分子的下调,包括VCAM-1,ICAM-1,NF-κB的p50亚基(p50),和MCP-1mRNA和蛋白质水平,H3K18ac水平显著下降。与这些一致,PCAF的过表达增强了炎症分子的表达。此外,PCAF缺乏减少了棕榈酸诱导的H3K18ac在ICAM-1和MCP-1启动子上的募集,并抑制了棕榈酸诱导的这些炎症分子的上调。总之,目前的工作表明,PCAF在通过H3K18ac调节炎症分子中起着至关重要的作用,这为炎症相关的肾脏疾病提供了潜在的治疗靶点。
Kidney diseases, including chronic kidney disease (CKD) and acute kidney injury (AKI), are associated with inflammation. The mechanism that regulates inflammation in these renal injuries remains unclear. Here, we demonstrated that p300/CBP-associated factor (PCAF), a histone acetyltransferase, was overexpressed in the kidneys of db/db mice and lipopolysaccharide (LPS)-injected mice. Moreover, elevated histone acetylation, such as H3K18ac, and up-regulation of some inflammatory genes, such as ICAM-1, VCAM-1, and MCP-1, were found upon these renal injuries. Furthermore, increased H3K18ac was recruited to the promoters of ICAM-1, VCAM-1, and MCP-1 in the kidneys of LPS-injected mice. In vitro studies demonstrated that PCAF knockdown in human renal proximal tubule epithelial cells (HK-2) led to downregulation of inflammatory molecules, including VCAM-1, ICAM-1, p50 subunit of NF-κB (p50), and MCP-1 mRNA and protein levels, together with significantly decreased H3K18ac level. Consistent with these, overexpression of PCAF enhanced the expression of inflammatory molecules. Furthermore, PCAF deficiency reduced palmitate-induced recruitment of H3K18ac on the promoters of ICAM-1 and MCP-1, as well as inhibited palmitate-induced upregulation of these inflammatory molecules. In summary, the present work demonstrates that PCAF plays an essential role in the regulation of inflammatory molecules through H3K18ac, which provides a potential therapeutic target for inflammation-related renal diseases.