| Autor: |
Adam J. Rauckhorst, Gabriela Vasquez Martinez, Gabriel Mayoral Andrade, Hsiang Wen, Ji Young Kim, Aaron Simoni, Kranti A. Mapuskar, Prerna Rastogi, Emily J Steinbach, Michael L. McCormick, Bryan G. Allen, Navjot S. Pabla, Ashley R. Jackson, Mitchell C. Coleman, Douglas R. Spitz, Eric B. Taylor, Diana Zepeda-Orozco |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
bioRxiv |
| Popis: |
Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Tubular metabolism changes markedly following acute kidney injury (AKI), but which changes are adaptive versus maladaptive remain poorly understood. In publicly available data sets, we noticed a consistent downregulation of the mitochondrial pyruvate carrier (MPC) after AKI, which we experimentally confirmed. To test the functional consequences of MPC downregulation, we generated novel tubular epithelial cell-specificMpc1knockout (MPC TubKO) mice.13C-glucose tracing, steady-state metabolomic profiling, and enzymatic activity assays revealed that MPC TubKO coordinately increased activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, MPC TubKO decreased markers of kidney injury and oxidative damage and strikingly increased survival. Our findings suggest that decreased mitochondrial pyruvate uptake is a central adaptive response following AKI and raise the possibility of therapeutically modulating the MPC to attenuate AKI severity. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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