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RIPK3 promotes sepsis-induced acute kidney injury via mitochondrial dysfunction
Angara Sureshbabu1, Edwin Patino2, Kevin C Ma1
1Division of Pulmonary and Critical Care Medicine, and.
Abstract:
Sepsis causes acute kidney injury (AKI) in critically ill patients, although the pathophysiology remains unclear. The receptor-interacting protein kinase-3 (RIPK3), a cardinal regulator of necroptosis, has recently been implicated in the pathogenesis of human disease. In mice subjected to polymicrobial sepsis, we demonstrate that RIPK3 promotes sepsis-induced AKI. Utilizing genetic deletion and biochemical approaches in vitro and in vivo, we identify a potentially novel pathway by which RIPK3 aggravates kidney tubular injury independently of the classical mixed lineage kinase domain-like protein-dependent (MLKL-dependent) necroptosis pathway. In kidney tubular epithelial cells, we show that RIPK3 promotes oxidative stress and mitochondrial dysfunction involving upregulation of NADPH oxidase-4 (NOX4) and inhibition of mitochondrial complex I and -III, and that RIPK3 and NOX4 are critical for kidney tubular injury in vivo. Furthermore, we demonstrate that RIPK3 is required for increased mitochondrial translocation of NOX4 in response to proinflammatory stimuli, by a mechanism involving protein-protein interactions. Finally, we observed elevated urinary and plasma RIPK3 levels in human patients with sepsis-induced AKI, representing potential markers of this condition. In conclusion, we identify a pathway by which RIPK3 promotes kidney tubular injury via mitochondrial dysfunction, independently of MLKL, which may represent a promising therapeutic target in sepsis-induced AKI.
Insights
Receptor-interacting protein kinase-3 (RIPK3) exacerbates sepsis-induced acute kidney injury (AKI) by promoting oxidative stress and mitochondrial dysfunction, independent of necroptosis. Urinary and plasma RIPK3 levels may serve as biomarkers for sepsis-induced AKI.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Sepsis frequently causes acute kidney injury (AKI) in critically ill patients.
- The precise mechanisms underlying sepsis-induced AKI are not fully understood.
- Receptor-interacting protein kinase-3 (RIPK3), a key regulator of necroptosis, is implicated in various diseases.
Purpose of the Study:
- To investigate the role of RIPK3 in sepsis-induced AKI.
- To elucidate the molecular pathways through which RIPK3 contributes to kidney injury during sepsis.
- To identify potential diagnostic markers for sepsis-induced AKI.
Main Methods:
- Utilized mouse models of polymicrobial sepsis.
- Employed genetic deletion (RIPK3 knockout) and biochemical analyses.
- Investigated RIPK3's effects on oxidative stress, mitochondrial function, and NADPH oxidase-4 (NOX4) in kidney tubular epithelial cells in vitro and in vivo.
- Analyzed urinary and plasma RIPK3 levels in human sepsis patients with AKI.
Main Results:
- RIPK3 significantly promotes sepsis-induced AKI in mice.
- RIPK3 exacerbates kidney tubular injury independently of MLKL-dependent necroptosis.
- RIPK3 upregulates NOX4, induces oxidative stress, and impairs mitochondrial complex I and III activity in kidney tubular cells.
- RIPK3 facilitates NOX4 mitochondrial translocation via protein-protein interactions.
- Elevated RIPK3 levels were detected in the urine and plasma of human patients with sepsis-induced AKI.
Conclusions:
- RIPK3 drives kidney tubular injury in sepsis through a novel pathway involving mitochondrial dysfunction and NOX4, independent of MLKL.
- RIPK3 and NOX4 are critical mediators of kidney damage in sepsis-induced AKI.
- Urinary and plasma RIPK3 levels show potential as biomarkers for sepsis-induced AKI, suggesting RIPK3 as a therapeutic target.
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