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The kidney senses mitochondrial-derived DAMPs to induce sterile inflammatory responses
| Content Provider | Semantic Scholar |
|---|---|
| Author | Pulskens, Wilco P. C. Butter, Loes M. Teske, Gwendoline J. D. Duitman, Jan Willem Florquin, Sandrine Juffermans, Nicole P. Leemans, Jaklien C. |
| Copyright Year | 2012 |
| Abstract | Systemic inflammation can cause severe collateral damage including the development of acute kidney injury. Inflammation is induced by different pattern recognition receptors (PRRs) of the innate immune system that sense damageassociated molecular patterns (DAMPs) that are released upon tissue injury. Mitochondria are a source of DAMPs and are thought to form a molecular link between tissue injury and inflammation in trauma patients. The role of the kidney herein remained however unstudied. Hence, in this study we investigated the role of renal tissue in sensing mitochondrial derived DAMPs to elicit inflammatory responses that may lead to renal injury and the impact of mitochondrial DNA on systemic inflammation and acute kidney injury (AKI). Primary renal tubular epithelial cells (TECs) were stimulated with necrotic supernatant or purified mitochondrial ligands, after which the inflammatory response was determined. Circulating mitochondrial DNA (mtDNA) was determined in plasma of mice subjected to ischemic AKI. Renal function and injury were assayed in mice that received an injection with purified mtDNA. The impact of systemic inflammatory response syndrome (SIRS) and AKI on the levels of plasma and urinary mtDNA was determined in patients on the Intensive Care Unit (ICU) and associated to inflammatory mediators. Our data reveal that renal TECs express several PRRs involved in sensing mitochondrial DAMPs and partly respond to necrotic cells in an mtDNA-dependent pathway. Mice that were subjected to ischemic AKI displayed elevated plasma mtDNA levels. Systemic administration of purified mtDNA provoked renal inflammation but did not affect renal function. Critically ill patients with SIRS demonstrated elevated levels of plasma and urinary mtDNA and proinflammatory cytokines compared to control ICU-patients. The presence of AKI did however not further statistically affect the levels of circulating or urinary mtDNA in SIRS patients. Our data demonstrate that the kidney recognizes and responds to mitochondrialderived ligands to initiate inflammation. This study further shows that experimental AKI is associated with high circulating mtDNA and that circulating mtDNA levels are associated with severity and outcome of systemic inflammation in critically ill patients. Together, these data suggests that mitochondrial DNA may form a link between tissue injury and inflammation. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://pure.uva.nl/ws/files/1608386/104616_07.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
