Endotoxin uptake by S1 proximal tubular segment causes oxidative stress in the downstream S2 segment

Rabih Kalakeche, Takashi Hato, Georges Rhodes, Kenneth Dunn, Tarek Ashkar (El-Achkar), Zoya Plotkin, Ruben M. Sandoval, Pierre Dagher

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Abstract

Gram-negative sepsis carries high morbidity and mortality, especially when complicated by acute kidney injury (AKI). The mechanisms of AKI in sepsis remain poorly understood. Here we used intravital two-photon fluorescence microscopy to investigate the possibility of direct interactions between filtered endotoxin and tubular cells as a possible mechanism of AKI in sepsis. Using wild-type (WT), TLR4-knockout, and bone marrow chimeric mice, we found that endotoxin is readily filtered and internalized by S1 proximal tubules through local TLR4 receptors and through fluid-phase endocytosis. Only receptor-mediated interactions between endotoxin and S1 caused oxidative stress in neighboring S2 tubules. Despite significant endotoxin uptake, S1 segments showed no oxidative stress, possibly as a result of the upregulation of cytoprotective heme oxygenase-1 and sirtuin-1 (SIRT1). Conversely, S2 segments did not upregulate SIRT1 and exhibited severe structural and functional peroxisomal damage. Taken together, these data suggest that the S1 segment acts as a sensor of filtered endotoxin, which it takes up. Although this may limit the amount of endotoxin in the systemic circulation and the kidney, it results in severe secondary damage to the neighboring S2 segments.

Original languageEnglish
Pages (from-to)1505-1516
Number of pages12
JournalJournal of the American Society of Nephrology
Volume22
Issue number8
DOIs
StatePublished - 2011

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Endotoxins
Oxidative Stress
Sirtuin 1
Acute Kidney Injury
Sepsis
Up-Regulation
Toll-Like Receptor 4
Heme Oxygenase-1
Renal Circulation
Endocytosis
Photons
Fluorescence Microscopy
Bone Marrow
Morbidity
Mortality

ASJC Scopus subject areas

  • Nephrology

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Endotoxin uptake by S1 proximal tubular segment causes oxidative stress in the downstream S2 segment. / Kalakeche, Rabih; Hato, Takashi; Rhodes, Georges; Dunn, Kenneth; Ashkar (El-Achkar), Tarek; Plotkin, Zoya; Sandoval, Ruben M.; Dagher, Pierre.

In: Journal of the American Society of Nephrology, Vol. 22, No. 8, 2011, p. 1505-1516.

Research output: Contribution to journalArticle

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