Abstract
Objective: Sepsis is the most common cause of acute kidney injury in critically ill patients; however, the mechanisms leading to acute kidney injury in sepsis remain elusive. Although sepsis has been considered an excessive systemic inflammatory response, clinical trials that inhibit inflammation have been shown to have no effect. The purpose of this study was to examine the pathophysiology of septic acute kidney injury focusing on immune responses and renal tubular cell apoptosis by providing an on-site quantitative comparison between septic-and ischemia/reperfusion-induced acute kidney injury. Design: Twenty-four hours after cecal ligation and puncture or ischemia/reperfusion injury, biochemical, histologic, and cytokine changes were compared in C57BL/6 mice. Apoptosis was assessed, and the effect of caspase 3 inhibition on renal function was also examined. The percentage of regulatory T cells and the effect of depletion were determined and compared with ischemia/reperfusion-induced acute kidney injury. The effect of interleukin-10 blocking was also compared. Measurements and Main Results: Despite comparable renal dysfunction, acute tubular necrosis or inflammation was minimal in septic kidneys. However, tubular cell apoptosis was prominent, and caspase 3 activity was positively correlated with renal dysfunction. A decrease in apoptosis by caspase 3 inhibitor resulted in attenuation of renal dysfunction. In assessment of systemic immunity, septic acute kidney injury was associated with an increase in interleukin-10, and also showed massive immune cell apoptosis with increased regulatory T cells. In contrast to ischemia/reperfusion injury in which depletion of regulatory T cells aggravated renal injury, depletion of regulatory T cells before cecal ligation and puncture resulted in renoprotection. In addition, blocking interleukin-10 rescued septic mice from the development of acute kidney injury, whereas it had no effect in ischemia/reperfusion injury. Conclusions: Pathogenesis of septic acute kidney injury is thought to be different from that of ischemia/ reperfusion-induced acute kidney injury. Our data showed a link between apoptosis, immune suppression, and the development of acute kidney injury during sepsis and suggest that strategies targeting apoptosis or enhancing immunity might be a potential therapeutic strategy for septic acute kidney injury.
| Original language | English |
|---|---|
| Pages (from-to) | 2997-3006 |
| Number of pages | 10 |
| Journal | Critical Care Medicine |
| Volume | 40 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2012 Nov 1 |
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Keywords
- acute kidney injury
- apoptosis
- immune suppression
- ischemia/reperfusion injury
- regulatory t cells
- sepsis
ASJC Scopus subject areas
- Critical Care and Intensive Care Medicine
Cite this
Distinct pathophysiologic mechanisms of septic acute kidney injury : Role of immune suppression and renal tubular cell apoptosis in murine model of septic acute kidney injury. / Lee, So Young; Lee, Yong Su; Choi, Hye Min; Ko, Yoon Sook; Lee, Hee Young; Jo, Sang Kyung; Cho, Won Yong; Kim, Hyoung Kyu.
In: Critical Care Medicine, Vol. 40, No. 11, 01.11.2012, p. 2997-3006.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Distinct pathophysiologic mechanisms of septic acute kidney injury
T2 - Role of immune suppression and renal tubular cell apoptosis in murine model of septic acute kidney injury
AU - Lee, So Young
AU - Lee, Yong Su
AU - Choi, Hye Min
AU - Ko, Yoon Sook
AU - Lee, Hee Young
AU - Jo, Sang Kyung
AU - Cho, Won Yong
AU - Kim, Hyoung Kyu
PY - 2012/11/1
Y1 - 2012/11/1
N2 - Objective: Sepsis is the most common cause of acute kidney injury in critically ill patients; however, the mechanisms leading to acute kidney injury in sepsis remain elusive. Although sepsis has been considered an excessive systemic inflammatory response, clinical trials that inhibit inflammation have been shown to have no effect. The purpose of this study was to examine the pathophysiology of septic acute kidney injury focusing on immune responses and renal tubular cell apoptosis by providing an on-site quantitative comparison between septic-and ischemia/reperfusion-induced acute kidney injury. Design: Twenty-four hours after cecal ligation and puncture or ischemia/reperfusion injury, biochemical, histologic, and cytokine changes were compared in C57BL/6 mice. Apoptosis was assessed, and the effect of caspase 3 inhibition on renal function was also examined. The percentage of regulatory T cells and the effect of depletion were determined and compared with ischemia/reperfusion-induced acute kidney injury. The effect of interleukin-10 blocking was also compared. Measurements and Main Results: Despite comparable renal dysfunction, acute tubular necrosis or inflammation was minimal in septic kidneys. However, tubular cell apoptosis was prominent, and caspase 3 activity was positively correlated with renal dysfunction. A decrease in apoptosis by caspase 3 inhibitor resulted in attenuation of renal dysfunction. In assessment of systemic immunity, septic acute kidney injury was associated with an increase in interleukin-10, and also showed massive immune cell apoptosis with increased regulatory T cells. In contrast to ischemia/reperfusion injury in which depletion of regulatory T cells aggravated renal injury, depletion of regulatory T cells before cecal ligation and puncture resulted in renoprotection. In addition, blocking interleukin-10 rescued septic mice from the development of acute kidney injury, whereas it had no effect in ischemia/reperfusion injury. Conclusions: Pathogenesis of septic acute kidney injury is thought to be different from that of ischemia/ reperfusion-induced acute kidney injury. Our data showed a link between apoptosis, immune suppression, and the development of acute kidney injury during sepsis and suggest that strategies targeting apoptosis or enhancing immunity might be a potential therapeutic strategy for septic acute kidney injury.
AB - Objective: Sepsis is the most common cause of acute kidney injury in critically ill patients; however, the mechanisms leading to acute kidney injury in sepsis remain elusive. Although sepsis has been considered an excessive systemic inflammatory response, clinical trials that inhibit inflammation have been shown to have no effect. The purpose of this study was to examine the pathophysiology of septic acute kidney injury focusing on immune responses and renal tubular cell apoptosis by providing an on-site quantitative comparison between septic-and ischemia/reperfusion-induced acute kidney injury. Design: Twenty-four hours after cecal ligation and puncture or ischemia/reperfusion injury, biochemical, histologic, and cytokine changes were compared in C57BL/6 mice. Apoptosis was assessed, and the effect of caspase 3 inhibition on renal function was also examined. The percentage of regulatory T cells and the effect of depletion were determined and compared with ischemia/reperfusion-induced acute kidney injury. The effect of interleukin-10 blocking was also compared. Measurements and Main Results: Despite comparable renal dysfunction, acute tubular necrosis or inflammation was minimal in septic kidneys. However, tubular cell apoptosis was prominent, and caspase 3 activity was positively correlated with renal dysfunction. A decrease in apoptosis by caspase 3 inhibitor resulted in attenuation of renal dysfunction. In assessment of systemic immunity, septic acute kidney injury was associated with an increase in interleukin-10, and also showed massive immune cell apoptosis with increased regulatory T cells. In contrast to ischemia/reperfusion injury in which depletion of regulatory T cells aggravated renal injury, depletion of regulatory T cells before cecal ligation and puncture resulted in renoprotection. In addition, blocking interleukin-10 rescued septic mice from the development of acute kidney injury, whereas it had no effect in ischemia/reperfusion injury. Conclusions: Pathogenesis of septic acute kidney injury is thought to be different from that of ischemia/ reperfusion-induced acute kidney injury. Our data showed a link between apoptosis, immune suppression, and the development of acute kidney injury during sepsis and suggest that strategies targeting apoptosis or enhancing immunity might be a potential therapeutic strategy for septic acute kidney injury.
KW - acute kidney injury
KW - apoptosis
KW - immune suppression
KW - ischemia/reperfusion injury
KW - regulatory t cells
KW - sepsis
UR - http://www.scopus.com/inward/record.url?scp=84868208280&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84868208280&partnerID=8YFLogxK
U2 - 10.1097/CCM.0b013e31825b912d
DO - 10.1097/CCM.0b013e31825b912d
M3 - Article
C2 - 22878677
AN - SCOPUS:84868208280
VL - 40
SP - 2997
EP - 3006
JO - Critical Care Medicine
JF - Critical Care Medicine
SN - 0090-3493
IS - 11
ER -