Deficiency of apoptosis‐stimulating protein two of p53 ameliorates acute kidney injury induced by ischemia reperfusion in mice through upregulation of autophagy

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.

Autophagy and Inflammation Regulation in Acute Kidney Injury

“…In addition, the treatment of ASPP2 +/+ and ASPP2 +/− mice with 3-MA or vehicle showed that the protective effect of ASPP2 deficiency in AKI was reversed upon the inhibition of autophagy. These data suggest that downregulation of ASPP2 can ameliorate I/R-induced AKI by activating autophagy and inhibiting inflammation ( Ji et al, 2018 ). Acute zinc chloride treatment in rats exerted a renoprotective effect in ischemic AKI, attenuated endoplasmic reticulum (ER) stress, and inhibited the expression of Beclin-1 and LAMP-2, which was correlated with inhibition of the expression of apoptosis-related factors (caspase-9, caspase-3, and p-JNK) and inflammation-related factors (IL-1ß, IL-6, and MCP-1; Abdallah et al, 2018 ).…”

Fundc1-dependent mitophagy is obligatory to ischemic preconditioning-conferred renoprotection in ischemic AKI via suppression of Drp1-mediated mitochondrial fission

“…Although several studies argue that mitophagy (autophagy) is induced by IRI, a recent study using novel autophagy-reporter mice demonstrated that autophagy is inhibited within 24-h post-IRI with an augmented autophagy around 1-3d post-IRI [55]. This concept has been supported by recent reports that mitophagy is in fact inhibited in the setting of renal IRI [56,57]. Several mechanisms may potentially contribute to the discrepancies in mitophagy (autophagy) activation/deactivation under IRI, including animal age [58], species or strains [58], and oxidative stress status [59].…”

Genomic Fabric Remodeling in Metastatic Clear Cell Renal Cell Carcinoma (ccRCC): A New Paradigm and Proposal for a Personalized Gene Therapy Approach

“…Overexpression of TASOR is expected to have the following major effects in PTA: -Down-regulation of three members of the general transcription factor IIH, polypeptide (GTF2H1/2C_2/5); degradation of GTF2H1 (a.k.a. P62) was associated with enhanced apoptosis and autophagy [74].…”