Myeloid Differentiation Protein 2 Mediates Angiotensin II-Induced Liver Inflammation and Fibrosis in Mice

Abstract

Angiotensin II (Ang II) participates in the pathogenesis of liver injury. Our previous publications reported that myeloid differentiation protein 2 (MD2) mediates Ang II-induced cardiac and kidney inflammation by directly binding to Ang II. Thus, we hypothesize that MD2 is critical to Ang II-induced liver injury. Subcutaneous injections of Ang II for 8 weeks were adopted to build the liver injury model. With a specific MD2 inhibitor L6H21 and MD2 knockout mice, we reported that MD2 inhibition and knockout significantly mitigate liver inflammation and fibrosis in mice injected with Ang II. To be more specific, the functional and pathological damages induced by Ang II were mitigated by L6H21 or MD2 knockout. MD2 knockout or L6H21 administration inhibited the Ang II-induced upregulation of fibrosis markers, inflammatory cytokines, and adhesion molecules in gene or protein levels. The activation of NF-κB and Extracellular signal-regulated kinases (ERK) induced by Ang II was also reversed by L6H21 treatment or MD2 deficiency. Note that the co-immunoprecipitation study showed that L6H21 downregulated the ANG II-induced toll-like receptor 4 (TLR4)/MD2 complex in liver tissues while having no effects on MD2 expression. Our results reported the critical role of MD2 in the progress of liver injury and suggested that MD2 is a potential therapeutic target for liver injury.

Elevated Angiotensin-II Levels Contribute to the Pathogenesis of Open-Angle Glaucoma Via Inducing the Expression of Fibrosis-Related Genes in Trabecular Meshwork Cells Through a ROS/NOX4/SMAD3 Axis

“…Over the past decades, the presence of local RASs has been revealed in various tissues with the accompanying discovery that angiotensin II (ANGII) acts as a novel immunomodulator and profibrotic molecule 12 – 16 , 19 . In accordance, the hypothesis that a localized RAS contributes to eye homeostasis has been prominent 23 .…”

“…In addition to the circulatory system that regulates urgent cardiovascular responses, tissue-localized RAS have been shown to influence long-term changes in certain organs 12 . For instance, elevated levels of angiotensin II (ANGII) induces skeletal muscle atrophy along with fibrosis in lung, liver, and kidney tissues 13 – 16 together with promoting reactive oxygen species (ROS)-mediated stress, senescence, and inflammation 17 – 20 . Intriguing, RAS components appear to be also expressed in the eye with possible connections made to the development of eye disease 21 – 24 .…”

RNAseq analysis reveals transcriptome changes associated with the progression of non-alcoholic liver disease in livers fromEfcab4bknockout mice

“…In a mouse model of NASH, knockout of Ly96 significantly attenuated triglyceride accumulation, lipid peroxidation, inflammation and liver fibrosis 57 . Similarly an angiotensin II liver injury mouse model displayed significantly reduced inflammation and fibrosis 58 . B4GALT1 is significantly down regulated in the livers of patients with HCC and reducing B4GALT1 enhanced HCC cell migration and invasion in vitro and promoted lung metastasis of HCC in NOD/SCID mice 59 .…”

RNA-seq analysis reveals transcriptome changes associated with the progression of non-alcoholic liver disease in livers from Efcab4b knockout mice

“…In a mouse model of NASH, knockout of Ly96 significantly attenuated triglyceride accumulation, lipid peroxidation, inflammation and liver fibrosis 52 . Similarly an angiotensin II liver injury mouse model displayed significantly reduced inflammation and fibrosis 53 . B4GALT1 is significantly down regulated in the livers of patients with HCC and reducing B4GALT1 enhanced HCC cell migration and invasion in vitro and promoted lung metastasis of HCC in NOD/SCID mice 54 .…”