PTEN protects kidney against acute kidney injury by alleviating apoptosis and promoting autophagy via regulating HIF1-α and mTOR through PI3K/Akt pathway.

Phosphatase and tensin homolog (PTEN) deleted on human chromosome 10 is a tumor suppressor with bispecific phosphatase activity, which is often involved in the study of energy metabolism and tumorigenesis. PTEN is recently reported to participate in the process of acute injury. However, the mechanism of PTEN in Ischemia-Reperfusion Injury (IRI) has not yet been clearly elucidated. In this study, mice with bilateral renal artery ischemia-reperfusion and HK-2 cells with hypoxia/reoxygenation (H/R) were used as acute kidney injury models. We demonstrated that PTEN was downregulated in IRI-induced kidney as well as in H/R-induced HK-2 cells. By silencing and overexpressing PTEN with si-PTEN RNA and PHBLV-CMV-PTEN-flag lentivirus before H/R, we found that PTEN protected HK-2 cells against H/R-induced injury reflected by the change in cell activity and the release of LDH. Furthermore, we inhibited HIF1-α with PX-478 and inactivated mTOR with Rapamycin before the silence of PTEN in H/R model. Our data indicated that the renoprotective effect of PTEN worked via PI3K/Akt/mTOR pathway and PI3K/Akt/HIF1-α pathway, hence alleviating apoptosis and improving autophagy respectively. Our findings provide valuable insights into the molecular mechanism underlying renoprotection of PTEN on autophagy and apoptosis induced by renal IRI, which offers a novel therapeutic target for the treatment of AKI.

Wang Y ，Wang X ，Wang H ，Bao J ，Jia N ，Huang H ，Li A ... -  《-》

MicroRNA‑93 inhibits the apoptosis and inflammatory response of tubular epithelial cells via the PTEN/AKT/mTOR pathway in acute kidney injury.

Zhan Y ，Zhu M ，Liu S ，Lu J ，Ni Z ，Cai H ，Zhang W ... -  《-》

Leptin relieves ischemia/reperfusion induced acute kidney injury through inhibiting apoptosis and autophagy.

Li S ，Zhuang K ，He Y ，Deng Y ，Xi J ，Chen J ... -  《-》

Apoptosis repressor with caspase recruitment domain deficiency accelerates ischemia/reperfusion (I/R)-induced acute kidney injury by suppressing inflammation and apoptosis: The role of AKT/mTOR signaling.

Acute kidney injury (AKI) is a significant medical problem worldwide. Ischemia-reperfusion (I/R) injury of the kidney is a major cause of AKI. However, the pathogenesis that contributes to renal I/R injury is still unclear. Apoptosis repressor with caspase recruitment domain (ARC) is abundantly expressed in various tissues, and has been reported to play a strong protective role during pathological processes. Our results indicated that ARC expression was decreased in the reperfused kidneys. ARC deficiency markedly accelerated renal dysfunction, promoted reperfusion-regulated tubular epithelial cell apoptosis, and enhanced the vulnerability of kidney to I/R damage. Furthermore, in the kidney samples of mice underwent renal I/R injury, ARC knockout significantly accelerated the expression levels of inflammatory factors, including interleukin (IL)-1β, IL-6, tumor necrosis factor a (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and IL-2. In addition, renal I/R injury-induced apoptosis was further exacerbated in ARC-deficient mice through promoting the expression of cleaved Caspase-3 and poly (ADP-ribose) polymerase (PARP). From the molecular level, ARC deletion obviously accelerated mitochondrial injury, as evidenced by the further decreased adenosine triphosphate (ATP) levels and mitochondrial potential in hypoxia-reoxygenation (H/R)-treated cells. Moreover, ARC knockout exacerbated AKI through activating phosphorylated protein kinase B (AKT), mammalian target of Rapamycin (mTOR) and p53, whereas reducing phosphorylated glycogen synthase kinase 3β (GSK3β). Of note, blocking AKT/mTOR signaling markedly attenuated inflammation, mitochondrial damage and apoptosis stimulated by H/R in ARC knockdown cells. In summary, our results suggested that ARC played a pivotal role in the pathogenesis of AKI induced by renal I/R operation through regulating AKT/mTOR signaling.

Yingjie K ，Haihong Y ，Lingwei C ，Sen Z ，Yuanting D ，Shasha C ，Liutong P ，Ying W ，Min Z ... -  《-》

C1q/TNF-related protein 6 (CTRP6) attenuates renal ischaemia-reperfusion injury through the activation of PI3K/Akt signalling pathway.

C1q/TNF-related protein 6 (CTRP6) is a member of the CTRP family that has been reported to exhibit a nephroprotective effect. However, the role of CTRP6 in renal ischaemia/reperfusion (I/R) injury (IRI) remains unclear. In the present study, we aimed to explore the protective effect of CTRP6 in renal IRI and the potential mechanism. We found that CTRP6 expression was markedly decreased in the kidneys of mice subjected to I/R and HK-2 cells in response to hypoxia/reoxygenation (H/R) stimulation. Recombinant CTRP6 protein protected against renal I/R injury by the reduction of blood urea nitrogen (BUN) and creatinine levels. The increased production of ROS and malondialdehyde (MDA), as well the decreased activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) caused by H/R induction were mitigated by CTRP6 in HK-2 cells. The caspase-3 activity and apoptotic rate were both decreased in CTRP6-overexpressing HK-2 cells. In addition, we also found that knockdown of CTRP6 aggravated H/R-caused oxidative stress and cell apoptosis in HK-2 cells. Moreover, CTRP6 overexpression enhanced the H/R-stimulated activation of PI3K/Akt pathway in HK-2 cells. Inhibition of PI3K reversed the nephroprotective effects of CTRP6 in HK-2 cells. Taken together, CTRP6 exerted protective effects against H/R-caused oxidative injury in HK-2 cells via activating the PI3K/Akt pathway.

Xiang H ，Xue W ，Li Y ，Zheng J ，Ding C ，Dou M ，Wu X ... -  《-》