scholarly journals Nonesterified free fatty acids enhance the inflammatory response in renal tubules by inducing extracellular ATP release

2020 ◽  
Vol 319 (2) ◽  
pp. F292-F303
Author(s):  
Hong Sun ◽  
Zilin Sun ◽  
Zac Varghese ◽  
Yinfeng Guo ◽  
John F. Moorhead ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Inflammatory Response ◽  
Free Fatty Acids ◽  
P2x7 Receptor ◽  
Atp Release ◽  
Extracellular Atp ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Tubular Cells ◽  
Purinergic P2x7 Receptor

In proteinuric renal diseases, excessive plasma nonesterified free fatty acids bound to albumin can leak across damaged glomeruli to be reabsorbed by renal proximal tubular cells and cause inflammatory tubular cells damage by as yet unknown mechanisms. The present study was designed to investigate these mechanisms induced by palmitic acid (PA; one of the nonesterified free fatty acids) overload. Our results show that excess PA stimulates ATP release through the pannexin 1 channel in human renal tubule epithelial cells (HK-2), increasing extracellular ATP concentration approximately threefold compared with control. The ATP release is dependent on caspase-3/7 activation induced by mitochondrial reactive oxygen species. Furthermore, extracellular ATP aggravates PA-induced monocyte chemoattractant protein-1 secretion and monocyte infiltration of tubular cells, enlarging the inflammatory response in both macrophages and HK-2 cells via the purinergic P2X7 receptor-mammalian target of rapamycin-forkhead box O1-thioredoxin-interacting protein/NOD-like receptor protein 3 inflammasome pathway. Hence, PA increases mitochondrial reactive oxygen species-induced ATP release and inflammatory stress, which cause a “first hit,” while ATP itself is a “second hit” in amplifying the renal tubular inflammatory response. Thus, inhibition of ATP release or the purinergic P2X7 receptor may be an approach to reduce renal inflammation and improve renal function.

scholarly journals Pannexin1 contributes to pathophysiological ATP release in lipoapoptosis induced by saturated free fatty acids in liver cells

2012 ◽  
Vol 303 (10) ◽  
pp. C1034-C1044 ◽  
Author(s):  
Feng Xiao ◽  
Shar L. Waldrop ◽  
Al-karim Khimji ◽  
Gordan Kilic
Keyword(s):  
Fatty Acids ◽  
Liver Injury ◽  
Free Fatty Acids ◽  
Atp Release ◽  
Liver Cells ◽  
Extracellular Atp ◽  
Pcr Analysis ◽  
Dependent Manner ◽  
Hepatic Inflammation ◽  
Atp Concentration

Hepatocyte lipoapoptosis induced by saturated free fatty acids (FFA) contributes to hepatic inflammation in lipotoxic liver injury, and the cellular mechanisms involved have not been defined. Recent studies have shown that apoptosis in nonhepatic cells stimulates ATP release via activation of pannexin1 (panx1), and extracellular ATP functions as a proinflammatory signal for recruitment and activation of the inflammatory cells. However, it is not known whether lipoapoptosis stimulates ATP release in liver cells. We found that lipoapoptosis induced by saturated FFA stimulated ATP release in liver cells that increased extracellular ATP concentration by more than fivefold above the values observed in healthy cells. This sustained pathophysiological ATP release was not dependent on caspase-3/7 activation. Inhibition of c-Jun NH2-terminal kinase (JNK), a key mediator of lipoapoptosis, with SP600125 blocked pathophysiological ATP release in a dose-dependent manner. RT-PCR analysis indicated that panx1 is expressed in hepatocytes and multiple liver cell lines. Notably, inhibition of panx1 expression with short hairpin (sh)RNA inhibited in part pathophysiological ATP release. Moreover, lipoapoptosis stimulated uptake of a membrane impermeable dye YoPro-1 (indicative of panx1 activation), which was inhibited by panx1 shRNA, probenecid, and mefloquine. These results suggest that panx1 contributes to pathophysiological ATP release in lipoapoptosis induced by saturated FFA. Thus panx1 may play an important role in hepatic inflammation by mediating an increase in extracellular ATP concentration in lipotoxic liver injury.

scholarly journals Iron Loading Exaggerates the Inflammatory Response to the Toll-like Receptor 4 Ligand Lipopolysaccharide by Altering Mitochondrial Homeostasis

2017 ◽  
Vol 127 (1) ◽  
pp. 121-135 ◽  
Author(s):  
Konrad Hoeft ◽  
Donald B. Bloch ◽  
Jan A. Graw ◽  
Rajeev Malhotra ◽  
Fumito Ichinose ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Inflammatory Response ◽  
Critically Ill Patients ◽  
Reactive Oxygen ◽  
Iron Loading ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Mitochondrial Mass ◽  
Mitochondrial Homeostasis ◽  
Mitochondrial Superoxide

Abstract Background Perioperative and critically ill patients are often exposed to iron (in the form of parenteral-iron administration or blood transfusion) and inflammatory stimuli, but the effects of iron loading on the inflammatory response are unclear. Recent data suggest that mitochondrial reactive oxygen species have an important role in the innate immune response and that increased mitochondrial reactive oxygen species production is a result of dysfunctional mitochondria. We tested the hypothesis that increased intracellular iron potentiates lipopolysaccharide-induced inflammation by increasing mitochondrial reactive oxygen species levels. Methods Murine macrophage cells were incubated with iron and then stimulated with lipopolysaccharide. C57BL/6 wild-type mice were intraperitoneally injected with iron and then with lipopolysaccharide. Markers of inflammation and mitochondrial superoxide production were examined. Mitochondrial homeostasis (the balance between mitochondrial biogenesis and destruction) was assessed, as were mitochondrial mass and the proportion of nonfunctional to total mitochondria. Results Iron loading of mice and cells potentiated the inflammatory response to lipopolysaccharide. Iron loading increased mitochondrial superoxide production. Treatment with MitoTEMPO, a mitochondria-specific antioxidant, blunted the proinflammatory effects of iron loading. Iron loading increased mitochondrial mass in cells treated with lipopolysaccharide and increased the proportion of nonfunctional mitochondria. Iron loading also altered mitochondrial homeostasis to favor increased production of mitochondria. Conclusions Acute iron loading potentiates the inflammatory response to lipopolysaccharide, at least in part by disrupting mitochondrial homeostasis and increasing the production of mitochondrial superoxide. Improved understanding of iron homeostasis in the context of acute inflammation may yield innovative therapeutic approaches in perioperative and critically ill patients.

scholarly journals 293 Different impacts of saturated and unsaturated free fatty acids on lipid synthesis and inflammatory response in sebocytes in culture

2016 ◽  
Vol 136 (9) ◽  
pp. S211 ◽  
Author(s):  
E. Flori ◽  
A. Mastrofrancesco ◽  
M. Ottaviani ◽  
M. Ludovici ◽  
C. Zouboulis ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Inflammatory Response ◽  
Free Fatty Acids ◽  
Lipid Synthesis
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