J Korean Med Sci.  2012 May;27(5):547-552. 10.3346/jkms.2012.27.5.547.

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

• Lee JA
• Choi JW
• In JH
• Jung HS
• Kim YS
• Jeon YS
• Kang YJ
• Kim DW
• Lim YG
• Park JH
• Joo JD

• KMID: 1372799
• DOI: http://doi.org/10.3346/jkms.2012.27.5.547

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 alpha, 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.

Keyword

Cytoprotective Proteins; Ischemic Preconditioning (IPC); Ischemia and Reperfusion (IR) Injury; Proinflammatory Cytokines

MeSH Terms

Animals
Intercellular Adhesion Molecule-1/genetics/metabolism
*Ischemic Preconditioning
Kidney/drug effects/metabolism/pathology/physiopathology
Liver/blood supply/drug effects/physiopathology
Male
Mice
Mice, Inbred C57BL
Nitric Oxide Synthase Type II/metabolism
Phosphorylation
Proto-Oncogene Proteins c-akt/metabolism
Reactive Oxygen Species/metabolism
Reperfusion Injury/*metabolism/pathology/prevention & control
Tiopronin/pharmacology
Tumor Necrosis Factor-alpha/genetics/metabolism

Figure

• 

  Fig. 1 Changes of inducible nitric oxide synthase (iNOS), phosphorylated Akt (pAkt) and total Akt from left renal cortices of mice subjected to sham operation (n = 8), 15 min (n = 8) or 24 hr (n = 8) after hepatic IPC, and 15 min (n = 8) or 24 hr (n = 8) after pretreated N-(2-mercaptopropionyl)-glycine (MPG) and hepatic IPC. (A) Representative immunoblots. (B) Densitometric quantifications of relative band intensities. *P < 0.05 vs sham, †P < 0.05 vs IPC operated. Error bars = µ SEM.

• 

  Fig. 2 Changes of proinflammatory cytokine, TNFα and ICAM1 from left renal cortices of mice subjected to sham operation (n = 8), renal IR group (n = 8), hepatic IPC + IR group (n = 8) and MPG-hepatic IPC + IR group (n = 8). (A) Representative RT-PCR images. (B) Densitometric quantifications of band intensities. *P < 0.05 vs sham group, †P < 0.05 vs IR group, ‡P < 0.05 vs IPC + IR group. TNFα, tumor necrosis factor α; ICAM1, intercellular adhesion molecule 1; IPC, ischemic preconditioning; IR, ischemia and reperfusion injury; MPG, N-(2-mercaptopropionyl)-glycine.

• 

  Fig. 3 Plasma creatinine levels in mice subjected to sham operation (n = 8), renal IR group (n = 8), hepatic IPC + IR group (n = 8) and MPG-hepatic IPC + IR group (n = 8). *P < 0.001 vs sham group, †P < 0.001 vs IR group, ‡P < 0.001 vs IPC + IR group. IPC, ischemic preconditioning; IR, ischemia and reperfusion injury; MPG, N-(2-mercaptopropionyl)-glycine.

• 

  Fig. 4 Representative HE stained photomicrographs of the kidney (magnification, × 200). (A) Outer medulla of a sham-operated mouse. (B) Mouse subjected to IR. (C) Mouse with hepatic IPC + IR. (D) Mouse with MPG-hepatic IPC + IR. IPC, ischemic preconditioning; IR, ischemia and reperfusion injury; MPG, N-(2-mercaptopropionyl)-glycine.

• 

  Fig. 5 Jablonski grading scale scores of outer medullary area for the histologic appearance of acute tubular necrosis in sham-operated mice (n = 8), mice subjected IR (n = 8), hepatic IPC + IR group (n = 8) and MPG-hepatic IPC + IR group (n = 8). *P < 0.001 vs sham group, †P < 0.001 vs IR group, ‡P < 0.001 vs IPC + IR group. IPC, ischemic preconditioning; IR, ischemia and reperfusion injury; MPG, N-(2-mercaptopropionyl)-glycine.

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