MiR-155 Is Involved In Renal Ischemia-Reperfusion Injury Via Regulating Renal Tubular Cell Pyroptosis

Renal ischemia-Reperfusion injury due to renal transplantation,liver transplantation and heminephrectomy is a major cause of acute kidney injury^[1].During renal ischemia-Reperfusion injury,the death of renal tubular cell and subsequent inflammatory responses contribute the development and progression of this injury.Pyroptosis is a pro-inflammatory programmed cell death^[2].unlike apoptosis or necrosis,Pyroptosis is characterized by rapid plasma membrane rupture and the release of pro-inflammatory intracellular contents.Caspase-1dependence is a definitive feature of pyroptosis.MicroRNAs are endogenous,small non-coding RNAs of approximately 19–22 nucleotides in length that is Involved in a wide range of biological processes^[3].In our study,An in vivo rat model of renal IRI was established.For the in vitro study,the cultured human renal proximal tubular cell line HK-2 was subjected to 24 h of hypoxia?5%CO2,1%O2,and 94%N2?followed by12 h of reoxygenation?5%CO2,21%O2,and 74%N2?.We found that during IRI in renal tissue and HRI in HK2 cells the expression of MiR-155was significantly up-regulated,while caspase-1,IL-1?and IL-18 were remarkly increased.Moreover over-expression of miR-155 resulted in increased levels of caspase-1,IL-1?and IL-18,whereas knockdown of miR-155 attenuated the inflammatory cell death of HK2 cells,indicating that anti-miR-155 could be a strategy for the prevention of renal pyroptosis.In further study,we found that miR-155 promoted renal tubular cell pyroptosis via down-regulating FoxO3a and its downstream protein ARC.More importantly,We performed a series of functional studies to determine the link between miR-155 and FoxO3a,finding that FoxO3a is a direct target of miR-155.in Conclusions,Our study proposes a new signaling pathway of miR-155/FoxO3a/ARC leading to renal pyroptosis under ischemia/reperfusion injury conditions.Renal ischemia-Reperfusion injury due to renal transplantation,liver transplantation and heminephrectomy is a major cause of acute kidney injury[1].During renal ischemia-Reperfusion injury,the death of renal tubular cell and subsequent inflammatory responses contribute the development and progression of this injury.Pyroptosis is a pro-inflammatory programmed cell death [2].unlike apoptosis or necrosis,Pyroptosis is characterized by rapid plasma membrane rupture and the release of pro-inflammatory intracellular contents.Caspase-1 dependence is a definitive feature of pyroptosis.Micro RNAs areendogenous,small non-coding RNAs of approximately 19–22 nucleotides in length that is Involved in a wide range of biological processes[3].In our study,An in vivo rat model of renal IRI was established.For the in vitro study,the cultured human renal proximal tubular cell line HK-2 was subjected to 24 h of hypoxia?5% CO2,1% O2,and 94% N2?followed by 12 h of reoxygenation?5% CO2,21% O2,and 74% N2?.We found that during IRI in renal tissue and HRI in HK2 cells the expression of Mi R-155 was significantly up-regulated,while caspase-1,IL-1? and IL-18 were remarkly increased.Moreover over-expression of mi R-155 resulted in increased levels of caspase-1,IL-1? and IL-18,whereas knockdown of mi R-155 attenuated the inflammatory cell death of HK2 cells,indicating that anti-mi R-155 could be a strategy for the prevention of renal pyroptosis.In further study,we found that mi R-155 promoted renal tubular cell pyroptosis via down-regulating Fox O3 a and its downstream protein ARC.More importantly,We performed a series of functional studies to determine the link between mi R-155 and Fox O3 a,finding that Fox O3 a is a direct target of mi R-155.in Conclusions,Our study proposes a new signaling pathway of mi R-155/Fox O3a/ARC leading to renal pyroptosis under ischemia/reperfusion injury conditions.