Abstract
Acute kidney injury (AKI) has become a common disorder with a high risk of morbidity and mortality, which remains major medical problem without reliable and effective therapeutic intervention. Apoptosis‐stimulating protein two of p53 (ASPP2) is a proapoptotic member that belongs to p53 binding protein family, which plays a key role in regulating apoptosis and cell growth. However, the role of ASPP2 in AKI has not been reported. To explore the role of ASPP2 in the progression of AKI, we prepared an AKI mouse model induced by ischaemia reperfusion (I/R) in wild‐type (ASPP2+/+) mice and ASPP2 haploinsufficient (ASPP2+/−) mice. The expression profile of ASPP2 were examined in wild‐type mice. The renal injury, inflammation response, cellular apoptosis and autophagic pathway was assessed in ASPP2+/+ and ASPP2+/− mice. The renal injury, inflammation response and cellular apoptosis was analysed in ASPP2+/+ and ASPP2+/− mice treated with 3‐methyladenine or vehicle. The expression profile of ASPP2 showed an increase at the early stage while a decrease at the late stage during renal injury. Compared with ASPP2+/+ mice, ASPP2 deficiency protected mice against renal injury induced by I/R, which mainly exhibited in slighter histologic changes, lower levels of blood urea nitrogen and serum creatinine, and less apoptosis as well as inflammatory response. Furthermore, ASPP2 deficiency enhanced autophagic activity reflecting in the light chain 3‐II conversion and p62 degradation, while the inhibition of autophagy reversed the protective effect of ASPP2 deficiency on AKI. These data suggest that downregulation of ASPP2 can ameliorate AKI induced by I/R through activating autophagy, which may provide a novel therapeutic strage for AKI.
Highlights
Acute kidney injury (AKI) is well known as a worldwide public health concern with high morbidity, mortality and healthcare costs
We found that the mRNA expression levels of IL‐1β, IL‐6 and TNF‐α were significantly decreased in ASPP2+/− mice compared with ASPP2+/+ mice (Figure 3C)
We identified that downregulation of ASPP2 protected mice against AKI by enhancing autophagy, which further suppresses inflammatory response and cellular apoptosis in mouse models
Summary
Acute kidney injury (AKI) is well known as a worldwide public health concern with high morbidity, mortality and healthcare costs. Apoptosis‐stimulating protein two of p53 (ASPP2), known as 53BP2L, is a proapoptotic regulator of p53‐binding protein family.[6] It was first identified as a tumor suppressor and an activator of p53 family members,[7,8] and play a critical role in regulating apoptosis and cell growth.[9]. A few studies on ASPP2 in kidney indicated that ASPP2 may play an important role in the renal desease.[10]. Based on the information all above, we hypothesized that ASPP2 played a vital role in the progression of AKI through autophagic pathways. To confirm this speculation, we used a classical renal I/R model to study the effect of ASPP2 on AKI and its regulatory mechanism
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