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Cannabinoid-2 receptor activation ameliorates hepatorenal syndrome

Authors:

Eszter Trojnar, Katalin Erdelyi,Csaba Matyas, Suxian Zhao, Janos Paloczi, Partha Mukhopadhyay, Zoltan V.Varga, Gyorgy Hasko, Pal Pacher


Published in Free Radical Biology and Medicine

May 2020

Abstract

Study rationale:
Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease characterized by the rapid decline of kidney function. Herein, we explored the therapeutic potential of targeting the cannabinoid-2 receptor (CB2-R) utilizing a commonly used mouse model of liver fibrosis and hepatorenal syndrome (HRS), induced by bile duct ligation (BDL).

Methods:
Gene expression analysis, histological evaluation, determination of serum levels of renal injury-biomarkers were used to characterize the BDL-induced organ injury; laser speckle analysis to measure microcirculation in the kidneys.

Key Results:
We found that liver injury triggered marked inflammation and oxidative stress in the kidneys of BDL-operated mice. We detected pronounced histopathological alterations with tubular injury paralleled with increased inflammation, oxidative/nitrative stress and fibrotic remodeling both in hepatic and renal tissues as well as endothelial activation and markedly impaired renal microcirculation. This was accompanied by increased CB2-R expression in both the liver and the kidney tissues of diseased animals. A selective CB2-R agonist, HU-910, markedly decreased numerous markers of inflammation, oxidative stress and fibrosis both in the liver and in the kidneys. HU-910 also attenuated markers of kidney injury and improved the impaired renal microcirculation in BDL-operated mice.

Conclusions:
Our results suggest that oxidative stress, inflammation and microvascular dysfunction are key events in the pathogenesis of BDL-associated renal failure. Furthermore, we demonstrate that targeting the CB2-R by selective agonists may represent a promising new avenue to treat HRS by attenuating tissue and vascular inflammation, oxidative stress, fibrosis and consequent microcirculatory dysfunction in the kidneys.

Open Access

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DOI: doi.org/10.1016/j.freeradbiomed.2019.11.027

Citation:

Trojnar, E., Erdelyi, K., Matyas, C., Zhao, S., Paloczi, J., Mukhopadhyay, P., … & Pacher, P. (2020). Cannabinoid-2 receptor activation ameliorates hepatorenal syndrome. Free Radical Biology and Medicine, 152, 540-550.