Chen Tianxin, Fang Zhendong, Zhu Jianfen, Lv Yinqiu, Li Duo, Pan Jingye
Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Key Laboratory of Intelligent Critical Care and Life Support Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Front Med (Lausanne). 2022 Jun 6;9:890782. doi: 10.3389/fmed.2022.890782. eCollection 2022.
Sepsis-induced AKI (SIAKI) is the most common complication with unacceptable mortality in hospitalized and critically ill patients. The pathophysiology of the development of SIAKI is still poorly understood. Our recent work has demonstrated the role of signal transducer and activator of transcription 3 (STAT3) pathways in regulating inflammation and coagulation in sepsis. We hypothesized that STAT3 activation has a critical role in early-stage SIAKI. The early-stage SIAKI model was established in cecal ligation and puncture (CLP) mice, which recapitulates the clinical and renal pathological features of early-stage AKI patients. Brush border loss (BBL) was the specific pathological feature of acute tubular injury in early-stage AKI. The role of STAT3 signaling and angiotension system in early-stage SIAKI was evaluated. The STAT3 activation (increased pSTAT3) and increased angiotensin-converting enzyme 2 (ACE2) expressions were observed in CLP mice. The low responsive expressions of pSTAT3 and ACE2 to septic inflammation in CLP AKI mice were associated with BBL. Correlation analysis of proteins' expressions showed pSTAT3 expression was significantly positively related to ACE2 expression in CLP mice. Reduced pSTAT3 after S3I201 intervention, which blocked STAT3 phosphorylation, decreased ACE2 expression, and exacerbated tubular injury in early-stage SIAKI. Our data indicate that endogenous increase of ACE2 expression upregulated by STAT3 activation in early-stage SIAKI play protective role against acute tubular injury.
脓毒症诱导的急性肾损伤（SIAKI）是住院患者和危重症患者中最常见且死亡率高得令人难以接受的并发症。SIAKI发生发展的病理生理学仍未得到充分理解。我们最近的研究表明信号转导和转录激活因子3（STAT3）通路在脓毒症炎症和凝血调节中发挥作用。我们推测STAT3激活在早期SIAKI中起关键作用。通过盲肠结扎和穿刺（CLP）小鼠建立早期SIAKI模型，该模型概括了早期急性肾损伤患者的临床和肾脏病理特征。刷状缘丢失（BBL）是早期急性肾损伤中急性肾小管损伤的特异性病理特征。评估了STAT3信号和血管紧张素系统在早期SIAKI中的作用。在CLP小鼠中观察到STAT3激活（pSTAT3增加）和血管紧张素转换酶2（ACE2）表达增加。CLP急性肾损伤小鼠中pSTAT3和ACE2对脓毒症炎症的低反应性表达与BBL有关。蛋白质表达的相关性分析显示，CLP小鼠中pSTAT3表达与ACE2表达显著正相关。S3I201干预后pSTAT3降低，该干预阻断了STAT3磷酸化，降低了ACE2表达，并加重了早期SIAKI中的肾小管损伤。我们的数据表明，早期SIAKI中由STAT3激活上调的内源性ACE2表达增加对急性肾小管损伤起保护作用。
