Dopamine receptor D2 inhibition alleviates diabetic hepatic stellate cells fibrosis by regulating the TGF‐β1/Smads and NFκB pathways

Abstract

Diabetic hepatic fibrosis (DHF) is a progressive liver disease and a chronic complication of diabetes mellitus. The main cause of DHF is the activation of quiescent hepatic stellate cells (HSCs) by high glucose stimulation. Dopamine receptor D2 (DRD2)‐mediated dopamine signalling can be involved in the regulation of diabetic liver disease, but the exact role of DRD2 in DHF is still poorly understood. This study aimed to investigate the protective effect of DRD2 inhibition on diabetic liver fibrosis and the potential mechanism. We established both streptozotocin (STZ)‐induced type 1 diabetes (T1D, fed for 20 weeks) rat model and high glucose (HG, 40 mmol/L)‐stimulated HSCs model. The results from both the rats with STZ and the HSCs treated with HG showed increased expression of DRD2, NOX‐5, inflammation‐related proteins (IL‐6 and TNFα) and fibrosis‐related proteins (TGF‐β1, CO‐Ⅰ/Ⅲ/ IV, MMP‐2/9 and fibronectin). In vivo, the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total antioxidant capacity (T‐AOC) levels were significantly increased, and hematoxylin‐eosin (HE) staining, Masson staining, and electron microscopy revealed liver lesions and hepatocyte injury. In addition, HG‐treated HSCs exhibited altered oxidative stress ‐ related indexes, including superoxide dismutase (SOD), malondialdehyde (MDA) and reactive oxygen species (ROS), changed and abnormally proliferated in vitro. TGF‐β1, the phosphorylated Smad2, nuclear NFκB‐p65, phosphorylated NFκB‐p65 and phosphorylated IκBα were also increased. Interestingly, haloperidol (DRD2 inhibitor) and n‐acetyl‐L‐cysteine (NAC, an active oxygen scavenger) reduced the above‐mentioned changes. In conclusion, DRD2 inhibition can reduce diabetic HSCs oxidative damage and fibrotic proliferation partly via the TGF‐β1/Smads and NFκB pathways.

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“…It has been previously suggested that dopamine receptor D2 antagonists, such as, prochlorperazine dimaleate, exert anti-fibrotic effects in models of diabetic hepatic fibrosis and non-alcoholic steatohepatitis induced liver fibrogenesis by regulating TGF-β1/Smad in hepatic stellate cells, and decreasing YAP levels in macrophages, respectively [ 59 , 60 ]. To our knowledge this pathway has not been investigated in PD.…”

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“…Zhao et al. found that DRD2 can be inhibited by TGF‐β1/Smarts and that the NF‐κB pathway partially reduces oxidative damage and the proliferation of hepatic stellate cells (HSCs) in diabetes 87 . Yan et al.…”

“…activation inactivated YAP/TAZ, switching activated fibroblasts from a fibrotic state of contraction, proliferation and matrix deposition to a matrix degradation-promoting state, thereby reversing liver fibrosis 86. Zhao et al found that DRD2 can be inhibited by TGF-β1/Smarts and that the NF-κB pathway partially reduces oxidative damage and the proliferation of hepatic stellate cells (HSCs) in diabetes 87. …”

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“…Another enzyme, CAT, accelerates the decomposition of H 2 O 2 into water and molecular oxygen ( Yan, Chen, & Zheng, 2017 ; B. B.; Zhao et al, 2021 ). Excessive blood glucose can hinder the antioxidant defense system, which influences the actions of antioxidant cascade enzymes in DM conditions (H. Q.…”