Eszter Trojnar1, Katalin Erdelyi2, Csaba Matyas3, Suxian Zhao4, Janos Paloczi5, Partha Mukhopadhyay6, Zoltan V Varga7, Gyorgy Hasko8, Pal Pacher9. 1. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism (NIAAA), 5625 Fishers Lane, 20852, Rockville, MD, USA. Electronic address: eszter.trojnar@nih.gov. 2. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism (NIAAA), 5625 Fishers Lane, 20852, Rockville, MD, USA. Electronic address: katalin.erdelyi@gmail.com. 3. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism (NIAAA), 5625 Fishers Lane, 20852, Rockville, MD, USA. Electronic address: csaba.matyas@nih.gov. 4. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism (NIAAA), 5625 Fishers Lane, 20852, Rockville, MD, USA. Electronic address: suxian.zhao@nih.gov. 5. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism (NIAAA), 5625 Fishers Lane, 20852, Rockville, MD, USA. Electronic address: janos.paloczi@nih.gov. 6. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism (NIAAA), 5625 Fishers Lane, 20852, Rockville, MD, USA. Electronic address: mpartha@mail.nih.gov. 7. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism (NIAAA), 5625 Fishers Lane, 20852, Rockville, MD, USA. Electronic address: vrgzltn@gmail.com. 8. Department of Anesthesiology, Columbia University, New York, NY, 10032, USA. Electronic address: gh2503@cumc.columbia.edu. 9. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism (NIAAA), 5625 Fishers Lane, 20852, Rockville, MD, USA. Electronic address: pacher@mail.nih.gov.
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.
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.
Authors: Mohanraj Rajesh; Partha Mukhopadhyay; Sándor Bátkai; Muhammad Arif; Zoltán V Varga; Csaba Mátyás; Janos Paloczi; Andrea Lehocki; György Haskó; Pal Pacher Journal: Geroscience Date: 2022-04-22 Impact factor: 7.581