Abstract
Ischemia-reperfusion (I/R) is a model of acute kidney injury (AKI) that is characterized by vasoconstriction, oxidative stress, apoptosis and inflammation. Previous studies have shown that activation of the renin-angiotensin system (RAS) may contribute to these processes. Angiotensin converting enzyme 2 (ACE2) metabolizes angiotensin II (Ang II) to angiotensin-(1–7), and recent studies support a beneficial role for ACE2 in models of chronic kidney disease. However, the role of ACE2 in models of AKI has not been fully elucidated. In order to test the hypothesis that ACE2 plays a protective role in AKI we assessed I/R injury in wild-type (WT) mice and ACE2 knock-out (ACE2 KO) mice. ACE2 KO and WT mice exhibited similar histologic injury scores and measures of kidney function at 48 hours after reperfusion. Loss of ACE2 was associated with increased neutrophil, macrophage, and T cell infiltration in the kidney. mRNA levels for pro-inflammatory cytokines, interleukin-1β, interleukin-6 and tumour necrosis factor-α, as well as chemokines macrophage inflammatory protein 2 and monocyte chemoattractant protein-1, were increased in ACE2 KO mice compared to WT mice. Changes in inflammatory cell infiltrates and cytokine expression were also associated with greater apoptosis and oxidative stress in ACE2 KO mice compared to WT mice. These data demonstrate a protective effect of ACE2 in I/R AKI.
Highlights
Ischemia-reperfusion (I/R) is an important cause of acute kidney injury (AKI) and a common occurrence in volume depleted or septic patients and in the setting of organ procurement for transplant
Compared to corresponding sham animals, there was no significant change in body weight after I/R in either WT mice or Angiotensin converting enzyme 2 (ACE2) KO mice (Table 1)
The mean value for tubular injury score after I/R tended to be higher in the ACE2 knock-out (ACE2 KO) mice compared to the WT mice, but the difference did not reach statistical significance (Figure 1B)
Summary
Ischemia-reperfusion (I/R) is an important cause of acute kidney injury (AKI) and a common occurrence in volume depleted or septic patients and in the setting of organ procurement for transplant. I/R often leads to significant kidney damage including progressive chronic kidney disease (CKD) [1,2,3]. Activation of the renin-angiotensin system (RAS) is implicated in most forms of kidney injury, and inhibiting its main effector, angiotensin II (Ang II), remains a cornerstone of therapy for progressive CKD [7,8]. The sequential action of renin and angiotensin converting enzyme (ACE) on angiotensinogen and angiotensin I respectively produces Ang II, which contributes to vasoconstriction, local tissue oxidative stress, inflammation, and fibrosis in CKD [9,10]. In previous studies of I/ R injury in rats, the RAS was found to be activated and kidney Ang II levels increased after I/R [11,12,13]
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