The Receptor for Advanced Glycation Endproducts (RAGE) Contributes to Severe Inflammatory Liver Injury in Mice

Abstract

Background: The receptor for advanced glycation end products (RAGE) is a multiligand receptor involved in a number of processes and disorders. While it is known that RAGE-signaling can contribute to toxic liver damage and fibrosis, its role in acute inflammatory liver injury and septic multiorgan failure is yet undefined. We examined RAGE in lipopolysaccharide (LPS) induced acute liver injury of D-galN sensitized mice as a classical model for tumor necrosis factor alpha (TNF-α) dependent inflammatory organ damage. Methods: Mice (Rage-/-and C57BL/6) were intraperitoneally injected with D-galN (300 mg/kg) and LPS (10 µg/kg). Animals were monitored clinically, and cytokines, damage associated molecular pattern molecules (DAMPs) as well as liver enzymes were determined in serum. Liver histology, hepatic cytokines as well as RAGE mRNA expression were analyzed. Cellular activation and functionality were evaluated by flow cytometry both in bone marrow-and liver-derived cells. Results: Genetic deficiency of RAGE significantly reduced the mortality of mice exposed to LPS/D-galN. Hepatocyte damage markers were reduced in Rage-/-mice, and liver histopathology was less severe. Rage-/-mice produced less pro-inflammatory cytokines and DAMPs in serum and liver. While immune cell functions appeared normal, TNF-α production by hepatocytes was reduced in Rage-/-mice. Conclusions: We found that RAGE deletion attenuated the expression of pro-inflammatory cytokines and DAMPs in hepatocytes without affecting cellular immune functions in the LPS/D-galN model of murine liver injury. Our data highlight the importance of tissue-specific RAGE-signaling also in acute inflammatory liver stress contributing to sepsis and multiorgan failure.

Increase of α-dicarbonyls in liver and receptor for advanced glycation end products on immune cells are linked to nonalcoholic fatty liver disease and liver cancer

“…It is important to mention that several studies recognized the role of RAGE in liver diseases, [60][61][62] including a very recent report on RAGE contribution to acute liver injury. 74 Although RAGE or the AGE/RAGE pathway have been already suggested as a potential target for therapeutic intervention in NASH and HCC, 58,59,62 our data extend the previous view and suggest that a targeted neutralization of α-DC and RAGE in livers may promise a stronger therapeutic potential. However, the latter still needs to be confirmed experimentally.…”

“…It is important to mention that several studies recognized the role of RAGE in liver diseases, 60–62 including a very recent report on RAGE contribution to acute liver injury. 74 …”

Advanced Glycation End-products Are Associated With Limited Range of Motion of the Shoulder Joint Following Rotator Cuff Tears

“…Increased ROS levels also induce mitochondrial DNA damage and activate caspases, thereby inducing apoptosis [29]. Increased levels of in ammatory cytokines and apoptosis result in brosis and tissue fragility [30]. In the present study, the increase in AGEs also resulted in increased gene expression of RAGE and NOX and increased ROS production.…”

Dysbiosis-Related Advanced Glycation Endproducts and Trimethylamine N-Oxide in Chronic Kidney Disease

“…Considering that RAGE also recognizes a wide range of DAMPs [ 93 ], it is likely that DAMPs derived from gut microbiota bind to RAGE, inducing immune cells to migrate and proliferate. With respect to acute inflammation, the genetic deletion of RAGE attenuated the hepatic expression of pro-inflammatory cytokines with a better survival rate compared to wild-type mice in LPS/D-galN-induced acute liver injury [ 95 ]. The outcome of a clinical research study supported the concept that there is a positive correlation between the expression levels of RAGE and E-selectin, endothelin-1, and TNF-α in septic AKI patients [ 96 ].…”