Bioinformatics-based identification of RAS disequilibrium involved in post-hemorrhagic shock mesenteric lymph return-mediated acute kidney injury in mice

Post-hemorrhagic shock mesenteric lymph (PHSML) return plays a critical role in the development of acute kidney injury (AKI). However, the molecular mechanism underlying PHSML-mediated AKI remains unclear. In this study, bioinformatics analysis identified key common targets of hemorrhagic shock and AKI, revealing significant enrichment in the renin-angiotensin system (RAS). To further investigate the role of RAS in PHSML-mediated AKI, we established mesenteric lymph duct ligation (MLDL) technology in mice and confirmed that MLDL alleviated hemorrhagic shock-induced AKI. Subsequently, male C57BL/6 mice subjected to hemorrhagic shock were treated with the angiotensin converting enzyme (ACE) inhibitor enalapril, angiotensin (1-7) (Ang (1-7)), and angiotensin II (Ang II) type 1 receptor (AT1R) inhibitor losartan. Additionally, mice with hemorrhage and MLDL were treated with Ang II, the Mas receptor (MasR) inhibitor A-779, or subjected to <i>Ace2</i> knockout. Renal histomorphology, expression of ACE, ACE2, AT1R, and MasR, and levels of Ang II and Ang (1-7) were assessed 4 h after resuscitation. The results demonstrated that hemorrhagic shock upregulated ACE and AT1R, while downregulating ACE2 and MasR, accompanied by elevated Ang II and reduced Ang (1-7). These adverse effects were partially reversed by MLDL, enalapril, Ang-(1-7), or losartan. Conversely, the beneficial role of MLDL was abolished by <i>Ace2</i> deficiency and the administration of Ang II and A-779. Collectively, these findings indicate that disequilibrium between the ACE-AngII-AT1R and ACE2-Ang (1-7)-MasR axes is implicated in PHSML-mediated AKI.