Abstract
Inflammatory cells contribute to the pathogenesis of renal ischemia-reperfusion injury (IRI). However, the signaling mechanisms underlying the infiltration of inflammatory cells into the kidney are not well understood. In this study, we examined the effects of phosphoinositide 3 kinase γ (PI3Kγ) on inflammatory cells infiltration into the kidney in response to ischemia-reperfusion injury. Compared with wild-type mice, PI3Kγ knockout mice displayed less IRI in the kidney with fewer tubular apoptotic cell. Furthermore, PI3Kγ deficiency decreased the number of infiltrated neutrophils, macrophages, and T cells in the kidney, which was accompanied by a decrease in the expression of pro-inflammatory cytokines in the kidney. Moreover, wild-type mice treated with AS-605240, a selective PI3Kγ inhibitor, displayed less tubular damage, accumulated fewer inflammatory cells, and expressed less proinflammatory molecules in the kidney following IRI. These results demonstrate that PI3Kγ has a critical role in the pathogenesis of kidney damage in IRI, indicating that PI3Kγ inhibition may serve as a potential therapeutic strategy for the prevention of ischemia-reperfusion-induced kidney injury.
Highlights
Acute kidney injury (AKI) is a common clinical disorder that can cause high morbidity and mortality
phosphoinositide 3 kinase γ (PI3Kγ)-positive staining in the kidney of KO mice was absent in both sham and Ischemia-reperfusion injury (IRI) groups indicating PI3Kγ was disrupted in the KO mice (Figure 1A,B)
We have demonstrated that genetic disruption or pharmacological inhibition of PI3Kγ suppresses inflammatory cell migration into the kidney, inhibits proinflammatory molecule production, and reduces tubular epithelial cell apoptosis in response to IRI
Summary
Acute kidney injury (AKI) is a common clinical disorder that can cause high morbidity and mortality. IRI causes damage to the kidney epithelial cells directly by hypoxia, and leads to the infiltration of inflammatory cells after ischemia This results in damage to the epithelial cells through the production of pro-inflammatory molecules, such as IL-1, TNF-alpha, MPC, IL-6 and adiponectin [3,4]. We demonstrated that the PI3Ks inhibitor could block the migration of macrophages induced by adiponectin in vitro, which contributed to the infiltration of inflammatory cells in the kidney with IRI [3]. These results suggest that PI3Ks may take part in the mechanism of kidney damage after IRI
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