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

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 1

Characterization of the endotoxemia model.

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Characterization of the endotoxemia model. (A) 10 mg/kg of i.p. LPS trig...
(A) 10 mg/kg of i.p. LPS triggers a rise in BUN and serum creatinine (Cr) at 18 hours; n = 4–11 per group. (B) Histological signs of injury in the LPS model are scarce. Left: Yellow arrows indicate individual proximal tubule cells with vacuolar changes; middle: yellow arrow points to a single necrotic cortical tubule; right: immunohistochemistry for cleaved caspase-3 (black arrows indicate positive cells) identifies scant apoptosis (representative images of n = 6 mice). Original magnification, ×40. (C) Color Doppler images (red indicates arterial flow; blue, venous flow) and renal artery blood flow (RBF) in n = 5 mice before and 18 hours after LPS administration. (D) BOLD MRI images for serial measurement of intrarenal oxygenation. Upper left: Axial R2* map of mouse with partial ligation of the left kidney and non-ligated contralateral kidney (R2* scale clipped at 80 Hz); upper right: axial R2* maps of non-ligated, pre-LPS, and 18 hours post-LPS kidney showing no major changes in overall or regional R2* values (R2* scale 0–60 Hz); bottom panel: overall R2* values for n = 5 mice before and 18 hours after LPS treatment showing no significant difference. *P < 0.05, **P < 0.01, ***P < 0.001 versus control or pre-LPS condition.