Limb ischemic preconditioning protects against contrast-induced nephropathy via renalase

• Limb ischemic preconditioning (IPC) leads to renalase upregulation in kidney tissue.
• Renalase is critically involved in limb IPC-elicited renal protection in contrast induced nephropathy.
• Limb IPC induces renalase upregulation via activation of the tumor necrosis factor α (TNFα)/ nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway.Renalase, a kidney-secreted protein, serves as extracellular pro-survival signals and has been reported to participate in the local ischemic preconditioning (IPC) induced renal protection against ischemia-reperfusion injury. Whether renalase contributes to the beneficial effects of limb IPC on contrast induced nephropathy (CIN) remains unknown. This study revealed that limb IPC induced reno-protection in CIN was at least in part dependent on increased renalase expression, which is evidenced by our observations that knockdown of renalase abolished reno-protective effects conferred by limb IPC. The upregulation of renalase elicited by limb IPC may be mediated by activation of TNFα/NF-κB pathway.

Clinical trials shows that remote ischemic preconditioning (IPC) can protect against contrast induced nephropathy (CIN) in risky patients, however, the exact mechanism is unclear. In this study, we explored whether renalase, an amine oxidase that has been previously shown to mediate reno-protection by local IPC, would also mediate the same effect elicited by remote IPC in animal model. Limb IPC was performed for 24 h followed by induction of CIN. Our results indicated that limb IPC prevented renal function decline, attenuated tubular damage and reduced oxidative stress and inflammation in the kidney. All those beneficial effects were abolished by silencing of renalase with siRNA. This suggests that similar to local IPC, renalase is also critically involved in limb IPC-elicited reno-protection. Mechanistic studies showed that limb IPC increased TNFα levels in the muscle and blood, and up-regulated renalase and phosphorylated IκBα expression in the kidney. Pretreatment with TNFα antagonist or NF-κB inhibitor, largely blocked renalase expression. Besides, TNFα preconditioning increased expression of renal renalase in vivo and in vitro, and attenuated H2O2 induced apoptosis in renal tubular cells. Collectively, our results suggest that limb IPC-induced reno-protection in CIN is dependent on increased renalase expression via activation of the TNFα/NF-κB pathway.