ACE2 Promoted by STAT3 Activation Has a Protective Role in Early-Stage Acute Kidney Injury of Murine Sepsis

Tianxin Chen; Zhendong Fang; Jianfen Zhu; Yinqiu Lv; Duo Li; Jingye Pan

doi:10.3389/fmed.2022.890782

ACE2 Promoted by STAT3 Activation Has a Protective Role in Early-Stage Acute Kidney Injury of Murine Sepsis

Front Med (Lausanne). 2022 Jun 6:9:890782. doi: 10.3389/fmed.2022.890782. eCollection 2022.

Authors

Tianxin Chen¹, Zhendong Fang², Jianfen Zhu³, Yinqiu Lv¹, Duo Li¹, Jingye Pan^{2

4}

Affiliations

¹ Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
² 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.
³ Department of Endoscopy Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁴ Department of ICU, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Abstract

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.

Keywords: STAT3; acute kidney injury; acute tubular injury; angiotensin-converting enzyme; sepsis.