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Aggravation of acute kidney injury by mPGES-2 down regulation is associated with autophagy inhibition and enhanced apoptosis.

ABSTRACT: The deletion of microsomal prostaglandin E synthase-2 (mPGES-2) does not affect in vivo PGE₂ production, and the function of this enzyme remains unknown until now. This study investigated the expression and roles of mPGES-2 in LPS induced acute kidney injury (AKI) both in vitro and in vivo. We found that mPGES-2 was up-regulated in kidney of mice with LPS induced AKI. Inhibition of mouse mpges2 gene expression exacerbated LPS-induced renal dysfunction, renal tubular cell damage and apoptosis, while inhibited kidney autophagy. Further cellular experiments showed that over-expression of mPGES-2 resulted in increased autophagy and decreased apoptosis rate of renal tubular epithelial cells. In addition, treatment with autophagy inhibitor 3-methyladenine could reverse the above-mentioned results. On the contrary, interference of mPGES-2 expression by siRNA decreased autophagy level but significantly increased apoptosis of tubular epithelial cells and treatment with autophagy inducer rapamycin can reverse these results. Overall, our study shows that mPGES-2 can protect renal tubular epithelial cells by regulating autophagy levels and aggravation of acute kidney injury by mPGES-2 down regulation is associated with autophagy inhibition and enhanced apoptosis.

SUBMITTER: Li T

PROVIDER: S-EPMC5579259 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Aggravation of acute kidney injury by mPGES-2 down regulation is associated with autophagy inhibition and enhanced apoptosis.

Li Ting T Liu Ying Y Zhao Jie J Miao Shuying S Xu Yunfei Y Liu Ke K Liu Meidong M Wang Guiliang G Xiao Xianzhong X

Scientific reports 20170831 1

The deletion of microsomal prostaglandin E synthase-2 (mPGES-2) does not affect in vivo PGE<sub>2</sub> production, and the function of this enzyme remains unknown until now. This study investigated the expression and roles of mPGES-2 in LPS induced acute kidney injury (AKI) both in vitro and in vivo. We found that mPGES-2 was up-regulated in kidney of mice with LPS induced AKI. Inhibition of mouse mpges2 gene expression exacerbated LPS-induced renal dysfunction, renal tubular cell damage and ap ...[more]

PMID: 28860615

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Project description:Seladin-1 is a neuroprotective protein selectively down-regulated in brain regions affected in Alzheimer disease (AD). Seladin-1 protects cells against beta-amyloid (Abeta) peptide 42- and oxidative stress-induced apoptosis activated by caspase-3, a key mediator of apoptosis. Here, we have employed RNA interference to assess the molecular effects of seladin-1 down-regulation on the beta-secretase (BACE1) function and beta-amyloid precursor protein (APP) processing in SH-SY5Y human neuroblastoma cells in both normal and apoptotic conditions. Our results show that approximately 60% reduction in seladin-1 protein levels, resembling the decrease observed in AD brain, did not significantly affect APP processing or Abeta secretion in normal growth conditions. However, under apoptosis, seladin-1 small interfering RNA (siRNA)-transfected cells showed increased caspase-3 activity on average by 2-fold when compared with control siRNA-transfected cells. Increased caspase-3 activity coincided with a significant depletion of the BACE1-sorting protein, GGA3 (Golgi-localized gamma-ear-containing ADP-ribosylation factor-binding protein), and subsequently augmented BACE1 protein levels and activity. Augmented BACE1 activity in turn correlated with the enhanced beta-amyloidogenic processing of APP and ultimately increased Abeta production. These adverse changes associated with decreased cell viability in seladin-1 siRNA-transfected cells under apoptosis. No changes in GGA3 or BACE1 levels were found after seladin-1 knockdown in normal growth conditions. Collectively, our results suggest that under stress conditions, reduced seladin-1 expression results in enhanced GGA3 depletion, which further leads to augmented post-translational stabilization of BACE1 and increased beta-amyloidogenic processing of APP. These mechanistic findings related to seladin-1 down-regulation are important in the context of AD as the oxidative stress-induced apoptosis plays a key role in the disease pathogenesis.

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Aggravation of acute kidney injury by mPGES-2 down regulation is associated with autophagy inhibition and enhanced apoptosis.

Publications

Aggravation of acute kidney injury by mPGES-2 down regulation is associated with autophagy inhibition and enhanced apoptosis.

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