TY - JOUR
T1 - PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice
AU - Tran, Mei
AU - Tam, Denise
AU - Bardia, Amit
AU - Bhasin, Manoj
AU - Rowe, Glenn C.
AU - Kher, Ajay
AU - Zsengeller, Zsuzsanna K.
AU - Reza Akhavan-Sharif, M.
AU - Khankin, Eliyahu V.
AU - Saintgeniez, Magali
AU - David, Sascha
AU - Burstein, Deborah
AU - Ananth Karumanchi, S.
AU - Stillman, Isaac E.
AU - Arany, Zoltan
AU - Parikh, Samir M.
PY - 2011/10/3
Y1 - 2011/10/3
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI58662
DO - 10.1172/JCI58662
M3 - Article
C2 - 21881206
AN - SCOPUS:80053402552
SN - 0021-9738
VL - 121
SP - 4003
EP - 4014
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 10
ER -