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

So Young Lee, Yong Su Lee, Hye Min Choi, Yoon Sook Ko, Hee Young Lee, Sang Kyung Jo, Won Yong Cho, Hyoung Kyu Kim

Research output: Contribution to journalArticle

53 Citations (Scopus)

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 languageEnglish
Pages (from-to)2997-3006
Number of pages10
JournalCritical Care Medicine
Volume40
Issue number11
DOIs
Publication statusPublished - 2012 Nov 1

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Acute Kidney Injury
Apoptosis
Kidney
Regulatory T-Lymphocytes
Sepsis
Reperfusion Injury
Caspase 3
Interleukin-10
Reperfusion
Ischemia
Punctures
Ligation
Immunity
Inflammation
Caspase Inhibitors
Inbred C57BL Mouse
Critical Illness
Necrosis
Clinical Trials
Cytokines

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 journalArticle

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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.",
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AU - Ko, Yoon Sook

AU - Lee, Hee Young

AU - Jo, Sang Kyung

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AU - Kim, Hyoung Kyu

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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.

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KW - apoptosis

KW - immune suppression

KW - ischemia/reperfusion injury

KW - regulatory t cells

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