Endothelial peroxisomal dysfunction and impaired pexophagy promotes oxidative damage in lipopolysaccharide-induced acute kidney injury.

Abstract

AIMS:

We examined that (a) how the endotoxic stress affects peroxisomal function and autophagic degradation of peroxisomes-pexophagy, (b) how a superimposed dysfunction of lysosomes and pexophagy modifies responses to lipopolysaccharide (LPS), and (c) the mechanisms of peroxisomal contribution to renal injury. To accomplish this, we used lysosome-defective Lyst-mice in vivo and primary endothelial cells in vitro, and compared the responses with wild-type (WT) littermates.

RESULTS:

LPS induced pexophagic degradation, followed by proliferation of peroxisomes in WT mice, which was abolished in Lyst-mice. Lyst-mice exhibited impaired activation of catalase, which together with preserved hydrogen peroxide-generating β-oxidation resulted in redox disequilibrium. LPS treatment induced a heightened inflammatory response, increased oxidative damage, and aggravated renal injury in Lyst-mice. Similarly, as in vivo, LPS-activated lysosomal (LYS) pexophagy and transiently repressed peroxisomes in vitro, supported by reduced peroxisomal density in the vicinity of lysosomes. Peroxisomal dynamics was also abolished in lysosome-defective cells, which accumulated peroxisomes with compromised functions and intraorganellar redox imbalance.

INNOVATION:

We demonstrated that pexophagy is a default response to endotoxic injury. However, when LYS dysfunction (a frequent companion of chronic diseases) is superimposed, recycling and functioning of peroxisomes are impaired, and an imbalance between hydrogen peroxide-generating β-oxidation and hydrogen peroxide-detoxifying catalase ensues, which ultimately results in peroxisomal burnout.

CONCLUSION:

Our data strongly suggest that pexophagy, a cellular mechanism per se, is essential in functional maintenance of peroxisomes during LPS exposure. Inhibition of pexophagy results in accumulation of impaired peroxisomes, redox disequilibrium, and aggravated renal damage.

• Authors: Radovan Vasko, Brian B Ratliff, Stefan Bohr, Ellen Nadel, Jun Chen, Sandhya Xavier, Praveen Chander, Michael S Goligorsky
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 19 Issue 3 Pg. 211-30 (Jul 20 2013) ISSN: 1557-7716 [Electronic] United States
• PMID: 23088293 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ATP-Binding Cassette Transporters
• Cytokines
• Gtf2h1 protein, mouse
• Inflammation Mediators
• Lipopolysaccharides
• Reactive Oxygen Species
• Transcription Factors
• Transcription Factor TFIIH
• Hydrogen Peroxide
• Catalase
• Acyl-CoA Oxidase

Topics

• ATP-Binding Cassette Transporters (metabolism)
• Acute Kidney Injury (chemically induced, metabolism)
• Acyl-CoA Oxidase (metabolism)
• Albuminuria
• Animals
• Autophagy
• Catalase (metabolism)
• Cytokines (blood)
• Disease Models, Animal
• Endothelial Cells (metabolism)
• Enzyme Activation
• Human Umbilical Vein Endothelial Cells (metabolism)
• Humans
• Hydrogen Peroxide (metabolism)
• Inflammation Mediators (blood)
• Lipopolysaccharides (adverse effects)
• Mice
• Models, Biological
• Oxidation-Reduction
• Oxidative Stress
• Peroxisomes (metabolism)
• Protein Transport
• Reactive Oxygen Species (metabolism)
• Transcription Factor TFIIH
• Transcription Factors (metabolism)