C-peptide ameliorates kidney injury following hemorrhagic shock.
Reperfusion injury following hemorrhagic shock is accompanied by the development of a systemic inflammatory state that may lead to organ failure. Insulin connecting peptide (C-peptide) has been shown to exert anti-inflammatory effects in sepsis and myocardial ischemia-reperfusion injury and to ameliorate renal dysfunction in diabetic animals. Hence, we investigated the effect of C-peptide on kidney injury after hemorrhagic shock. We hypothesized that C-peptide would exert renoprotective effects by blunting inflammation. Hemorrhagic shock was induced in male rats (3-4 months old) by withdrawing blood from the femoral artery to a mean arterial pressure of 50 mmHg. Animals were kept in shock for 3 h, at which time they were rapidly resuscitated by returning their shed blood. At the time of resuscitation and every hour thereafter, one group of animals received C-peptide (280 nmol/kg), whereas another group received vehicle. Hemorrhagic shock resulted in significant rise in plasma levels of creatinine and elevated kidney neutrophil infiltration as evaluated by myeloperoxidase activity in vehicle-treated rats in comparison with sham rats, thus suggesting kidney injury. Treatment with C-peptide significantly attenuated the rise in creatinine and kidney myeloperoxidase activity when compared with vehicle group. At a molecular level, these effects of C-peptide were associated with reduced expression of the c-Fos subunit and reduced activation of the proinflammatory kinases, extracellular signal-regulated kinase 1/2 (ERK 1/2), and c-Jun N-terminal kinase and subsequently reduced DNA binding of activator protein 1 in the kidney. Thus, our data suggest that C-peptide may exert renoprotective effects after hemorrhagic shock by modulating activator protein 1 signaling.
Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. ranjit.chima@cchmc.org
Ranjit S
RS
Chima
Giuseppe
G
Maltese
Timberly
T
Lamontagne
Giovanna
G
Piraino
Alvin
A
Denenberg
Michael
M
O'Connor
Basilia
B
Zingarelli
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002096:C-Peptide / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012771:Shock, Hemorrhagic / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D002096:C-Peptide; D003404:Creatinine; D009195:Peroxidase
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