PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice
Mei Tran,Denise Tam,Amit Bardia,Manoj Bhasin,Glenn C. Rowe,Ajay Kher,Zsuzsanna K. Zsengellér,M. Reza Akhavan-Sharif,Eliyahu V. Khankin,Magali Saint-Geniez,Sascha David,Deborah Burstein,S. Ananth Karumanchi,Isaac E. Stillman,Zoltan Arany,Samir M. Parikh +15 more
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TLDR
It is shown that endotoxemia reduces oxygen delivery to the kidney, without changing tissue oxygen levels, suggesting reduced oxygen consumption by the kidney cells, and that PGC-1α induction may be necessary for recovery from this disorder.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.read more
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Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development
Hyun Mi Kang,Seon Ho Ahn,Peter S. Choi,Yi-An Ko,Seung Hyeok Han,Frank Chinga,Ae Seo Deok Park,Jianling Tao,Kumar Sharma,James Pullman,Erwin P. Bottinger,Ira J. Goldberg,Katalin Susztak +12 more
TL;DR: It is found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and higher intracellular lipid deposition compared to controls, raising the possibility that correcting the metabolic defect in FAO may be useful for preventing and treating chronic kidney disease.
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Acute Kidney Injury.
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Cardiac angiogenic imbalance leads to peripartum cardiomyopathy
Ian S. Patten,Sarosh Rana,Sajid Shahul,Glenn C. Rowe,Cholsoon Jang,Laura Liu,Michele R. Hacker,Julie S. Rhee,John D. Mitchell,Feroze Mahmood,Philip E. Hess,Caitlin Farrell,Nicole Koulisis,Eliyahu V. Khankin,Suzanne D. Burke,Suzanne D. Burke,I. Tudorache,Johann Bauersachs,Federica del Monte,Denise Hilfiker-Kleiner,S. Ananth Karumanchi,S. Ananth Karumanchi,Zoltan Arany +22 more
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Mechanisms of Cardiac and Renal Dysfunction in Patients Dying of Sepsis
Osamu Takasu,Joseph P. Gaut,Eizo Watanabe,Kathleen To,R. Eliot Fagley,Brian Sato,Steve Jarman,Igor R. Efimov,Deborah Janks,Anil Srivastava,Sam B. Bhayani,Anne M. Drewry,Paul E. Swanson,Richard S. Hotchkiss,Richard S. Hotchkiss +14 more
TL;DR: Cell death is rare in sepsis-induced cardiac dysfunction, but cardiomyocyte injury occurs, and the degree of cell injury and death does not account for severity of sepsi-induced organ dysfunction.
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