Shuyan Kan , Qing Hou , Ruixiang Yang, Fan Yang, Mingchao Zhang, Zhihong Liu, Song Jiang
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引用次数: 0
摘要
背景组蛋白去乙酰化酶6(HDAC6)抑制剂CAY10603已被确定为治疗糖尿病肾病(DKD)的潜在治疗药物。本研究的目的是探讨 CAY10603 对急性肾损伤(AKI)和慢性肾脏疾病(CKD)小鼠的治疗效果。方法采用肾脏免疫组织学方法评估 HDAC6 在人类和小鼠肾脏样本中的表达水平。C57BL/6J小鼠腹腔注射脂多糖(LPS)诱导AKI;CD-1小鼠以腺嘌呤饮食诱导腺嘌呤肾病作为CKD模型。测定血清肌酐、血尿素氮和尿酸以反映肾功能;应用肾组织学评估肾损伤。结果HDAC6在AKI和CKD患者以及小鼠的肾小管上皮细胞(RTECs)中显著上调。在 LPS 诱导的 AKI 和腺嘌呤诱导的肾病小鼠模型中,CAY10603 表现出明显的保护作用,包括改善生化指标和病理变化。体内和体外研究显示,CAY10603能有效抑制由硫辛酸(Tg)--一种常用的内质网(ER)应激源--引发的UPR的活化转录因子6(ATF6)分支的激活。与这些发现一致的是,CAY10603 还能显著抑制 LPS 诱导的 AKI 和腺嘌呤诱导的肾病小鼠模型中 RTECs 的 ATF6 激活。
Inhibition of HDAC6 with CAY10603 alleviates acute and chronic kidney injury by suppressing the ATF6 branch of UPR
Background
Histone deacetylase 6 (HDAC6) inhibitor CAY10603 has been identified as a potential therapeutic agent for the treatment of diabetic kidney disease (DKD). The objective of this study was to investigate the therapeutic effects of CAY10603 in mice with acute kidney injury (AKI) and chronic kidney diseases (CKD).
Methods
Renal immunohistology was performed to assess the expression levels of HDAC6 in both human and mouse kidney samples. C57BL/6J mice were intraperitoneal injected with lipopolysaccharide (LPS) to induce AKI; CD-1 mice were fed with adenine diet to induce adenine-nephropathy as CKD model. Serum creatinine, blood urea nitrogen and uric acid were measured to reflect renal function; renal histology was applied to assess kidney damage. Western blot and immunohistology were used to analyze the unfolded protein response (UPR) level.
Results
HDAC6 was significantly upregulated in renal tubular epithelial cells (RTECs) of both AKI and CKD patients as well as mice. In the murine models of AKI induced by LPS and adenine-induced nephropathy, CAY10603 exhibited notable protective effects, including improvement in biochemical indices and pathological changes. In vivo and in vitro studies revealed that CAY10603 effectively suppressed the activation of activating transcription factor 6 (ATF6) branch of UPR triggered by thapsigargin (Tg), a commonly employed endoplasmic reticulum (ER) stressor. Consistent with these findings, CAY10603 also displayed substantial inhibition of ATF6 activation in RTECs from both murine models of LPS-induced AKI and adenine-induced nephropathy.
Conclusions
Collectively, these results suggest that CAY10603 holds promise as a potential therapeutic agent for both acute and chronic kidney injury.
期刊介绍:
Archives of Biochemistry and Biophysics publishes quality original articles and reviews in the developing areas of biochemistry and biophysics.
Research Areas Include:
• Enzyme and protein structure, function, regulation. Folding, turnover, and post-translational processing
• Biological oxidations, free radical reactions, redox signaling, oxygenases, P450 reactions
• Signal transduction, receptors, membrane transport, intracellular signals. Cellular and integrated metabolism.