Aldose reductase mediates endotoxin-induced production of nitric oxide and cytotoxicity in murine macrophages

Abstract

Aldose reductase (AR) is a ubiquitously expressed protein with pleiotrophic roles as an efficient catalyst for the reduction of toxic lipid aldehydes and mediator of hyperglycemia, cytokine, and growth factor-induced redox-sensitive signals that cause secondary diabetic complications. Although AR inhibition has been shown to be protective against oxidative stress signals, the role of AR in regulating nitric oxide (NO) synthesis and NO-mediated apoptosis has not been elucidated to date. We therefore investigated the role of AR in regulating lipopolysaccharide (LPS)-induced NO synthesis and apoptosis in RAW 264.7 macrophages. Inhibition or RNA interference ablation of AR suppressed LPS-stimulated production of NO and overexpression of iNOS mRNA. Inhibition or ablation of AR also prevented the LPS-induced apoptosis, cell cycle arrest, activation of caspase-3, p38-MAPK, JNK, NF-kappaB, and AP1. In addition, AR inhibition prevented the LPS-induced down-regulation of Bcl-xl and up-regulation of Bax and Bak in macrophages. L-Arginine increased and L-NAME decreased the severity of cell death caused by LPS and AR inhibitors prevented it. Furthermore, inhibition of AR prevents cell death caused by HNE and GS-HNE, but not GS-DHN. Our findings for the first time suggest that AR-catalyzed lipid aldehyde-glutathione conjugates regulate the LPS-induced production of inflammatory marker NO and cytotoxicity in RAW 264.7 cells. Inhibition or ablation of AR activity may be a potential therapeutic target in endotoximia and other inflammatory diseases.

Aldose reductase mediates retinal microglia activation

“…Therefore, understanding the mechanism of RMG activation is a necessity for preventing these ocular diseases. Ramana and colleagues conducted many studies showing that AR plays a key role in modulating inflammatory responses in macrophages [30–32]. In agreement with Ramana’s group, we previously demonstrated that either genetic ablation or pharmacological inhibition of AR attenuates endotoxin-induced inflammatory responses in macrophages and primary RMG [25, 26].…”

“…Recent studies also implicate AR in the pathogenesis of uveitis [25–27] and fibrotic changes associated with posterior capsular opacification [28, 29]. Genetic or pharmacological blockade of AR successfully alleviates inflammatory responses induced by endotoxin [25, 26, 30–32] or hyperglycemia [33–35]. Our previous study showed that genetic or pharmacological downregulation of AR prevents endotoxin-induced inflammatory responses in RMG primary cell cultures [26].…”

The complex role of iNOS in acutely rejecting cardiac transplants

“…This effect may not be peculiar to aldose reductase inhibitors but perhaps relative to the presence or absence of aldose reductase activity based on new studies using siRNA for aldose reductase. These studies show a diminished NO production and iNOS expression in LPS-treated macrophages [62].…”

Inhibition of Nitric Oxide and Prostaglandin E₂ Expression by Methanol Extract of <i>Polyopes affinis</i> in Lipopolysaccharide-stimulated BV2 Microglial Cells through Suppression of Akt-dependent NF-kB Activity and MAPK Pathway

“…In this study, we also found that MEPA suppresses the Aktdependent activation of NF-κB, suggesting that MEPA affects the regulation of the inflammatory signal cascade. Nevertheless, further work is required to substantiate these observations in light of the study that revealed the role of the transcriptional factor AP-1 expression of proinflammatory genes [21].…”