The current study investigated the role of ACE/ACE2 in the process of PHSML mediated kidney injury on the basis of previous studies. It was found that RAS imbalance occurred in hemorrhagic shock mice, which is characterized by ACE-Ang II-AT1R axis upregulation and ACE2-Ang (1–7)-MasR axis downregulation. The inhibition of ACE-Ang II-AT1R axis and MLDL reduced the kidney injury through the RAS balance reestablishment. Conversely, the inhibition of ACE2-Ang (1–7)-MasR abolished the beneficial effect of MLDL alleviating kidney injury. These results suggested that the imbalance of RAS is involved in the kidney injury mediated by PHSML.
Histological observation showed that the renal injury in the shock group was more severe than that in the sham group. After the treatment with Enalapril, Ang (1–7) and Losartan, this injury was alleviated significantly. Meanwhile, MLDL alleviated the kidney injury of mice following hemorrhagic shock. And the intervention of Ang II, A-779 and ACE2 gene knockout abolished the beneficial effects of MLDL. The results showed that the pathology of kidney changed according to changing the balance of ACE/ACE2 in mice.
ACE is an important component of RAS, which is expressed in glomerular and tubular. The expression of ACE in kidney increased significantly and participated in the process of kidney injury in sepsis . Our studies showed that hemorrhagic shock significantly increased the ACE and AT1R expressions and Ang level II in kidney, which were revered by the administrations of Enalapril, Losartan and Ang (1–7), respectively. These results indicate that changing the balance of ACE/ACE2 in mice could not only changes the expression of ACE in kidney, but also alleviates kidney injury by regulating the expressions of downstream receptors but the detailed mechanism remains to be further inquiried. Excessive Ang II leads to water-sodium retention, increased intraglomerular pressure, mesangial cells and mesangial matrix increased, causing renal function downregulation. The mechanism is related to the activation of AMPK/mTOR signaling, TLR4/NF-κB signaling and TGF-β signaling [9–11].
ACE2 is a newly discovered carboxypeptidase in recent years, which converts Ang II into protective Ang (1–7), which acts on MasR to effect. Our data demonstrated that hemorrhagic shock significantly decreased the ACE2 expression in kidney, which was significantly increased by the administration of Enalapril, Losartan and Ang (1–7), accompanying by increased expressions of MasR and Ang (1–7). Previous studies have shown that Enalapril upregulate the ACE2 expression and downregulate the ACE expression in the heart of spontaneously hypertensive rats . Klimas’ study reported that Losartan upregulate the ACE2 and MasR expressions in the kidney obtained from spontaneously hypertensive rats . These findings suggest that the above drugs can upregulate ACE2 and MasR expressions in the kidney, while downregulate the ACE expression. Its possible mechanism is inhibiting the activation of mitogen-activated protein kinase and NF-κB signalings [14, 15]. But its specific mechanism still needs to be further explored.
Previous experiments have confirmed that PHSML is one of the important factors of organs injury, and blocking PHSML return can reduce the organs injury [16–18]. In this study, the expressions of ACE and AT1R and Ang II level were decreased, while the expressions of ACE2 MasR and Ang (1–7) were increased in mesenteric lymphatic ligation group compared to the shock group. After administration of Ang II and MasR blocker A-779, the pathological changes of kidney in mesenteric lymphatic ligation group were significantly more severe than shock group, accompanied by the decreasing of ACE2 and MasR and increasing of ACE and AT1R. In addition, ACE2−/− mice was more severe histopathological changes than that of mesenteric lymphatic ligation mice, even the lower expression of MasR and Ang (1–7). These results suggest that MLDL alleviates the imbalance of ACE/ACE2 and pathological changes in kidney, but the mechanism by which MLDL regulating the components in RAS was not clear.
Collectively, the current investigation showed that hemorrhagic shock induced the unbalance of ACE/ACE2 in murine kidneys and acute kidney injury, the treatments of ACE/Ang II/AT1R inhibition and MLDL alleviated PHSML-mediated kidney and recovered the balance of ACE/ACE2. These results indicate that ACE/ACE2 imbalance is involved in PHSML mediated kidney injury, which is beneficial to elucidate the mechanism of PHSML mediated kidney injury and explore the treatment of kidney injury after hemorrhagic shock in the future.