Key result
In mice with cerulein-induced severe acute pancreatitis, ACE2 knock-out exacerbated inflammatory responses and necrosis, whereas ACE2 transgenic mice were more resistant to the challenge.
ACE2-ACE imbalance plays an important role in the pathogenesis of severe acute pancreatitis, with pancreatic ACE2 being a protective factor.
ACE2 protection in experimental pancreatitis is hypothesis-generating; leaves open translation to human disease.
New Findings What is the central question of this study? Angiotensin‐converting enzyme 2 (ACE2) degrades angiotensin II to angiotensin‐(1–7) and has recently been described to have an antagonistic effect on angiotensin‐converting enzyme (ACE) signalling. However, the specific underlying role of ACE2 in the pathogenesis of severe acute pancreatitis (SAP) is unclear. What is the main finding and its importance? Using wild‐type, ACE2 knock‐out and ACE2 transgenic mice, we show that ACE2–ACE imbalance plays an important role in the pathogenesis of SAP and that pancreatic ACE2 is an important factor in determining the severity of SAP. Angiotensin‐converting enzyme (ACE) and its effector peptide angiotensin II (Ang II) have been implicated in the pathogenesis of pancreatitis. Angiotensin‐converting enzyme 2 (ACE2) degrades Ang II to angiotensin‐(1–7) [Ang‐(1–7)] and has recently been described to have an antagonistic effect on ACE signalling. However, the specific underlying role of ACE2 in the pathogenesis of severe acute pancreatitis (SAP) is unclear. In the present study, the local imbalance of ACE and ACE2, as well as Ang II and Ang‐(1–7) expression, was compared in wild‐type (WT) and ACE2 knock‐out (KO) or ACE2 transgenic (TG) mice subjected to cerulein‐induced SAP. Serum amylase, tumour necrosis factor‐α, interleukin (IL)‐1β, IL‐6 and IL‐10 levels and histological morphometry were used to determine the severity of pancreatitis. In WT mice, pancreatic ACE and Ang II and serum Ang II expression increased ( P < 0.05), while pancreatic ACE2 and Ang‐(1–7) and serum Ang‐(1–7) levels were also significantly elevated ( P < 0.05) from 2 to 72 h after the onset of SAP. However, the ratio of pancreatic ACE2 to ACE expression was significantly reduced (from 1.46 ± 0.09 to 0.27 ± 0.05, P < 0.001) and paralleled the severity of pancreatitis. The Ace2 KO mice exhibited increased levels of tumour necrosis factor‐α, IL‐1β, IL‐6, multifocal coagulative necrosis and inflammatory infiltrate, and lower levels of serum IL‐10 and pancreatic Ang‐(1–7) (4.70 ± 2.13 versus 10.87 ± 2.51, P < 0.001) compared with cerulein‐treated WT mice at the same time point. Conversely, Ace2 TG mice with normal ACE expression were more resistant to SAP challenge as evidenced by a decreased inflammatory response, attenuated pathological changes and increased survival rates. These data suggest that the ACE2–ACE imbalance plays an important role in the pathogenesis of SAP and that pancreatic ACE2 is an important factor in determining the severity of SAP.
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Liu et al. (2014) studied Severe acute pancreatitis. ACE2 knock-out and ACE2 transgenic modification vs. Wild-type mice was evaluated on Severity of pancreatitis (inflammatory markers and histological morphometry) (p=<0.001). In mice with cerulein-induced severe acute pancreatitis, ACE2 knock-out exacerbated inflammatory responses and necrosis, whereas ACE2 transgenic mice were more resistant to the challenge.
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