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RIPK3 promotes sepsis-induced acute kidney injury via mitochondrial dysfunction
Angara Sureshbabu, … , Augustine M. K. Choi, Mary E. Choi
Angara Sureshbabu, … , Augustine M. K. Choi, Mary E. Choi
Published June 7, 2018
Citation Information: JCI Insight. 2018;3(11):e98411. https://doi.org/10.1172/jci.insight.98411.
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Research Article Cell biology Nephrology

RIPK3 promotes sepsis-induced acute kidney injury via mitochondrial dysfunction

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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.

Authors

Angara Sureshbabu, Edwin Patino, Kevin C. Ma, Kristian Laursen, Eli J. Finkelsztein, Oleh Akchurin, Thangamani Muthukumar, Stefan W. Ryter, Lorraine Gudas, Augustine M. K. Choi, Mary E. Choi

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Figure 1

Sepsis increases RIPK3 expression in kidney tubular epithelial cells.

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Sepsis increases RIPK3 expression in kidney tubular epithelial cells.
(A...
(A) Western blot for the expression of p-RIPK3, RIPK3, and p-MLKL in HK-2 cells treated with or without LPS (1 μg/ml) for the indicated times. (B) Western blot for the expression of p-RIPK3, RIPK3, and MLKL in kidney homogenates of WT mice at 6 hours after CLP or sham surgery. Western blots shown are representative results from 3 independent experiments. (C and D) Representative IHC images of RIPK3 (C) and RIPK3 (D) staining localized to the kidney tubular epithelial cells from Ripk3+/+ or Ripk3–/– mice at 6 hours after CLP or sham surgery. (n = 6 for Sham; n = 6 for CLP). Scale bars: 20 μm.

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