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 b-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 b-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. Antioxid. Redox Signal. 19,[211][212][213][214][215][216][217][218][219][220][221][222][223][224][225][226][227][228][229][230]

Peroxisomes and Kidney Injury

“…Our group demonstrated that systemic injection of a sublethal dose of endotoxin induces a biphasic response starting with a transient decrease followed by an increase of peroxisome numbers in the kidney of normal mice (102). Experimental studies revealed that peroxisomes have a half-life of 48 h and are mainly degraded by autophagy under basal conditions (44).…”

“…The loss of catalase activity during renal ischemia is largely caused by the inactivation of the enzyme. Ischemia-induced generation of H 2 O 2 , together with (102). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars intracellular acidosis, predisposes catalase to form an enzymatically inactive complex.…”

How the Innate Immune System Senses Trouble and Causes Trouble

“…It is proposed that proinflammatory cytokines generated from glomeruli could spread inflammation along the tubules through peritubular capillaries (85). Heightened PRR activation in the endothelium is another important source of inflammation (86,87), while properly activated endothelium is critical for mobilizing immune cells and clearing microbes (88). We also point out that because of the sentinel nature of innate immunity, studies have primarily focused on acute pathologic changes rather than long-term consequences of PRR activation, such as its role in fibrosis (89)(90)(91).…”

Peroxisomal Pex3 Activates Selective Autophagy of Peroxisomes via Interaction with the Pexophagy Receptor Atg30

“…A physiological association has been made between disease states and altered peroxisome turnover in primary endothelial cells, wherein impaired peroxisome homeostasis and function result from induced renal toxicity or sepsis (33). Artificial induction of pexophagy has been reported in mammalian cells by fusing ubiquitin moieties to PEX3 and PMP34 (34).…”