Hepatic Ischemic Preconditioning Provides Protection Against Distant Renal Ischemia and Reperfusion Injury in Mice

Abstract

We previously demonstrated that there are acute and delayed phases of renal protection against renal ischemia and reperfusion (IR) injury with renal ischemic preconditioning (IPC). This study assessed whether hepatic IPC could also reduce distant renal IR injury through the blood stream-mediated supply of reactive oxygen species (ROS). Male C57BL/6 mice were randomly divided into four groups: group I, sham operated including right nephrectomy; group II (IR), left renal ischemia for 30 min and reperfusion injury; group III (IPC-IR), hepatic ischemia for 10 min followed by 10 min of reperfusion before left renal IR injury; group IV (MPG - IPC + IR), pretreated with 100 mg/kg N-(2-mercaptopropionyl)-glycine (MPG) 15 min before hepatic IPC and left renal IR injury. Renal function, histopathologic findings, proinflammatory cytokines, and cytoprotective proteins were evaluated 15 min or 24 hr after reperfusion. Hepatic IPC attenuated the expression of proinflammatory cytokines, tumor necrosis factor α, intercellular adhesion molecule 1, and induced inducible nitric-oxide synthase, and the phosphorylation of Akt in the murine kidney. Renal function was better preserved in mice with hepatic IPC (group III) than groups II or IV. Hepatic IPC protects against distant renal IR injury through the blood stream-delivery of hepatic IPC-induced ROS, by inducing cytoprotective proteins, and by inhibiting inflammatory reactions.

Molecular Mechanisms of Renal Ischemic Conditioning Strategies

“…Ateş et al [17 ]demonstrated that rIPC significantly reduced the plasma concentration of TNF-α. Similarly, significantly lower levels of TNF-α mRNA as well as ICAM-1 mRNA in the kidney have been reported following rIPC [127]. This finding corresponds to results of an experimental study on the protective effect of rIC on liver grafts [138].…”

“…Furthermore, administration of morphine (a classic μ-opiod receptor agonist) in order to mimic the renoprotective effect of rIPC was unsuccessful [125]. In a study by Lee et al [127], administration of a free radical scavenger MPG abrogated the protective effect of rIPC. The authors suggest that the humoral trigger factor in this model were free oxygen radicals carried in the bloodstream.…”

“…No effect on either functional or molecular endpoints was detected. In a study by Lee et al [127], rIPC induced significantly higher levels of phosphorylated Akt and iNOS in the kidney, 15 min and 24 h after the conditioning stimulus, compared to the sham group. The role of HO-1 as an intracellular mediator in rIPerC was investigated by Soendergaard et al [126]; no significant differences in protein or mRNA levels in the groups were detected at 10 h posttransplant.…”

“…The molecular mechanisms and effects of rIC, which have been investigated, include trigger factors [124,125], intracellular mediators/effectors [95,126,127] and anti-oxidative stress actions [17,111,128,129,130] to systemic and local anti-inflammatory effects [17,131,132] as well as an anti-fibrotic effect [68]. Four studies reported only functional endpoints [19,133,134,135].…”

Ischemic preconditioning attenuates lipid peroxidation and apoptosis in the cecal ligation and puncture model of sepsis

“…Notably high histological lung and kidney injury scores have been observed in septic rats (62–65). IP attenuates lung and kidney histological injuries in ischemic conditions and Lee et al (66) histologically showed that hepatic IP is able to attenuate renal ischemic injury. It has been demonstrated that IP acts via A1 adenosine receptor activation (15,41).…”