Ischemic preconditioning attenuates ischemia/reperfusion-induced kidney injury by activating autophagy via the SGK1 signaling pathway.

Abstract

Ischemic preconditioning (IPC) has a strong renoprotective effect during renal ischemia/reperfusion (I/R) injury that is thought to relate to autophagy. However, the role of autophagy during IPC-afforded renoprotection and the precise mechanisms involved are unknown. In this study, an in vitro hypoxia/reoxygenation (H/R) model was established in which oxygen and glucose deprivation (OGD) was applied to renal cells for 15 h followed by reoxygenation under normal conditions for 30 min, 2 h or 6 h; transient OGD and subsequent reoxygenation were implemented before prolonged H/R injury to achieve hypoxic preconditioning (HPC). 3-Methyladenine (3-MA) was used to inhibit autophagy. In a renal I/R injury model, rats were subjected to 40 min of renal ischemia followed by 6 h, 12 h or 24 h of reperfusion. IPC was produced by four cycles of ischemia (8 min each) followed by 5 min of reperfusion prior to sustained ischemia. We found that IPC increased LC3II and Beclin-1 levels and decreased SQSTM/p62 and cleaved caspase-3 levels in a time-dependent manner during renal I/R injury, as well as increased the number of intracellular double-membrane vesicles in injured renal cells. IPC-induced renal protection was efficiently attenuated by pretreatment with 5 mM 3-MA. Pretreatment with IPC also dynamically affected the expression of SGK1/FOXO3a/HIF-1α signaling components. Moreover, knocking down SGK1 expression significantly downregulated phosphorylated-FOXO3a (p-FOXO3a)/FOXO3 and HIF-1α, suppressed LC3II and Beclin-1 levels, increased SQSTM/p62 and cleaved caspase-3 levels, and abolished the protective effect of IPC against I/R-induced renal damage. SGK1 overexpression efficiently increased p-FOXO3a/FOXO3 and HIF-1α levels, promoted the autophagy flux and enhanced the protective effect mediated by HPC. Furthermore, FOXO3a overexpression decreased HIF-1α protein levels, inhibited HIF-1α transcriptional activity and reduced the protective effect of IPC. Our study indicates that IPC can ameliorate renal I/R injury by promoting autophagy through the SGK1 pathway.

• Authors: Ying Xie, Daofang Jiang, Jing Xiao, Chensheng Fu, Zhenxing Zhang, Zhibin Ye, Xiaoli Zhang
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 3 Pg. 338 (03 01 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 29497029 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Beclin-1
• FOXO3 protein, rat
• Forkhead Box Protein O3
• Hypoxia-Inducible Factor 1, alpha Subunit
• Immediate-Early Proteins
• LC3 protein, rat
• Microtubule-Associated Proteins
• Sequestosome-1 Protein
• Sqstm1 protein, rat
• Protein Serine-Threonine Kinases
• serum-glucocorticoid regulated kinase

Topics

• Animals
• Autophagy
• Beclin-1 (genetics, metabolism)
• Forkhead Box Protein O3 (genetics, metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Immediate-Early Proteins (genetics, metabolism)
• Ischemic Preconditioning (methods)
• Kidney (metabolism)
• Kidney Diseases (etiology, genetics, metabolism, physiopathology)
• Male
• Microtubule-Associated Proteins (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (complications, genetics, metabolism, therapy)
• Sequestosome-1 Protein (genetics, metabolism)
• Signal Transduction