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PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice
Mei Tran, … , Zoltan Arany, Samir M. Parikh
Mei Tran, … , Zoltan Arany, Samir M. Parikh
Published September 1, 2011
Citation Information: J Clin Invest. 2011;121(10):4003-4014. https://doi.org/10.1172/JCI58662.
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Research Article Nephrology

PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice

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Abstract

Sepsis-associated acute kidney injury (AKI) is a common and morbid condition that is distinguishable from typical ischemic renal injury by its paucity of tubular cell death. The mechanisms underlying renal dysfunction in individuals with sepsis-associated AKI are therefore less clear. Here we have shown that endotoxemia reduces oxygen delivery to the kidney, without changing tissue oxygen levels, suggesting reduced oxygen consumption by the kidney cells. Tubular mitochondria were swollen, and their function was impaired. Expression profiling showed that oxidative phosphorylation genes were selectively suppressed during sepsis-associated AKI and reactivated when global function was normalized. PPARγ coactivator–1α (PGC-1α), a major regulator of mitochondrial biogenesis and metabolism, not only followed this pattern but was proportionally suppressed with the degree of renal impairment. Furthermore, tubular cells had reduced PGC-1α expression and oxygen consumption in response to TNF-α; however, excess PGC-1α reversed the latter effect. Both global and tubule-specific PGC-1α–knockout mice had normal basal renal function but suffered persistent injury following endotoxemia. Our results demonstrate what we believe to be a novel mechanism for sepsis-associated AKI and suggest that PGC-1α induction may be necessary for recovery from this disorder, identifying a potential new target for future therapeutic studies.

Authors

Mei Tran, Denise Tam, Amit Bardia, Manoj Bhasin, Glenn C. Rowe, Ajay Kher, Zsuzsanna K. Zsengeller, M. Reza Akhavan-Sharif, Eliyahu V. Khankin, Magali Saintgeniez, Sascha David, Deborah Burstein, S. Ananth Karumanchi, Isaac E. Stillman, Zoltan Arany, Samir M. Parikh

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Figure 6

Effects of TNF-α and heterologous PGC-1α expression on oxygen consumption and mitochondrial gene expression in human proximal tubular epithelial cells.

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Effects of TNF-α and heterologous PGC-1α expression on oxygen consumptio...
(A) Relative mRNA expression of PGC-1α and downstream electron transport components following the indicated treatments. (B) TNF-α dose- and time-dependently reduces oxygen consumption (pmol/min of O2 consumed) of confluent human renal proximal tubule cells. After measuring basal respiration, we applied oligomycin (OL) to block complex V, then 2,4-dinitrophenol (2,4-DNP) to uncouple mitochondria, then rotenone to inhibit complex I. (C) TNF-α–induced changes in basal respiration and uncoupled respiration. (D) Compared with backbone control adenovirus (Control), adenovirus encoding murine PGC-1α (Ad-PGC-1α) increases the expression of PGC-1α in the setting of TNF-α treatment (left) and prevents TNF-α–induced reductions in basal (middle) and uncoupled respiration (right; reported as pmol/min of O2 consumed). (E) Ad-PGC-1α restores the expression of downstream electron transport enzymes to non-TNF-α levels. Note that the PGC-1α measured is human, not mouse. n = 9 replicates per condition. **P < 0.01, ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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