Angiotensin II Type 2 Receptors (AT2R) for Rheumatoid Arthritis Treatment

Key words:

• Inflammation
• Synovium
• Arthritis
• Immune system
• Agonism

Introduction:

Rheumatoid arthritis (RA) is described as a chronic autoimmune disease that comprises of synovial damage, swelling and pain (Wang et al., 2019). It predominantly affects joint tissues, gradually causing dysfunction and deformation. (Wang et al., 2018). It instigates a variety of co-morbid conditions, as well as having high social cost.  The patient activity scale (developed by Wolfe et al via health questionnaire and 2 visual analogues for pain and total activity) places RA at a mean score of 3.4 out of a scale of 10, ranging from 1.7-5.7 for those who have not taken any medication (Toledano et al., 2019), indicating that individuals with RA do experience mild to intermediate discomfort in their daily lives. RA heritability has been estimated to contribute around 12-60% of the disease, incidences peaking at around 50 years of age (Macías-Segura et al., 2018). The renin-angiotensin system (RAS) is a hormonal system that regulates fluid homeostasis and blood pressure, being present in a variety of tissues such as the heart, kidneys, testicles, lungs, fatty tissue, as well as regulating tissue function. The main components of RAS, which comprise of Angiotensin-converting enzyme (ACE), Angiotensin I type 1 receptors (AT1R) and Angiotensin II type 2 receptors (AT2R), are expressed in both human and animal synovial tissues, contributing to the progression of RA (Wang et al., 2018). The expression of these mediators are associated with the degree of inflammation and RA severity. Angiotensin II produces its effects by binding to two key receptors: the AT1R which mediates tissue damage, and the AT2R which is considered to counteract the AT1R mediated effects (Marino et al., 2012).

Result evaluation:

The study by Terenzi et al. published in nature (2017), studies the effects of AT2R activation on dampening the pro-inflammatory and aggressive behavior of RA via its modulation by specific agonists. The authors first carried out an immuno-histological analysis on the synovial membrane section of 8 patients with RA and 8 patients with osteoarthritis (OA), detecting the expression of AT2R in either the synovial lining layer or the Synovial sub-lining layer. This analysis method employed by the authors allow them to visualize the optical density of target receptors/proteins in an ex-vivo system. The results  indicated that AT2R immunostaining was greater in the cells of RA synovial lining in comparison to OA cell synovial lining. The authors then went on to investigate the effects of pro-inflammatory cytokines (TNF- and IL-1, alone or in combination) on the expression ad modulation of AT2R in cultured fibroblast-like synoviocytes (FLS) from RA, OA and healthy synovium (via fluorescence immunochemistry and western blotting). Ex-vitro FLS cultures are an optimal medium to use for analysis due to FLS involvement  in the instigation and continuance of AR, as well as the ability to modulate the production of inflammation and joint destruction (Claudia et al., 2013). Therefore FLS cultures provide a close ex-vitro representation of the microenvironment in affected AR joints in comparison to healthy and OA joints. The results concluded that RA FLS  exhibited the highest expression levels of AT2R protein expression and stimulation with TNF- and IL-1 resulted in significantly higher levels in comparison to the OA and healthy FLS, concluding that in inflamed cells, AT2R expression may increase and more significant in AR-FLS. It must be acknowledged that the sample size of the study is relatively small thus even though the results seem substantial, a larger cohort of test subjects (with varying severity of arthritis) as well as an in vivo testing are needed to confirm the findings. Nonetheless, the results suggest that targeting AT2R may be more beneficial for AR patients, but still can be used to treat OA.

Figure 1: expression of angiotensin II type 2 receptor (AT2R) in fibroblast-like synoviocytes (FLS) of osteoarthritis (OA) and rheumatoid arthritis (RA) synovium in the presence of necrosis factor (TNF-) and interleukin (IL-1) in combination, as a percentage of healthy AT2R expression. (Terenzi et al., 2017).

AT2R agonism was also found to reduce gene expression of pro-inflammatory cytokines IL1B and IL6, decreasing their mRNA expression, however, did not affect TNF levels. They then went on to examine its effects on NF-B , being a major transcription activator in the pro-inflammatory cytokine genes. NF-B is known for its association with cytokine production and gene regulation in relation to inflammation (Ruiz-Ortega et al., 2001). It was discovered that activation of AT2R with the AT2R agonist CGP42112A followed a significant reduction in NF-B activity. Finally the ability for the AT2R agonist to influence RA-FLS migration and proliferation (at baseline or after treatment with TNF- and IL-1) was evaluated and concluded that the agonist decreases cell viability and wound healing capabilities. This was tested via WST-1 cell viability and wound healing assays. Although the invitro section of the study tested for the effects of AT2R agonism on gene expression of IL1B/IL6 and the ability of NF-B to bind to DNA, no detailed mechanisms were characterized in the study, however this is also related to the fact that no previous studies have investigated the association of AT2R with rheumatoid arthritis, thus, the molecular mechanisms of AT receptor subtypes have not been fully identified (Ruiz-Otega et al., 2001)

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The authors go on to explain the implications of a non-peptide agonist that has been recently developed named compound 21 (C21). A study by Sampson et al. investigated the effects of direct stimulation of AT2R with C21 and found that it prevented TNFα stimulated vascular inflammation (in vitro and in vitro). Therefore, this study suggest the potential use of a AT2R agonist, such as C21, for individuals with AR may provide an alternate or additional treatment to reduce inflammation and progression of the disease. However, further studies are needed to explore its mechanisms, desirable dosages and any side effects associated before therapeutic use in humans.

Conclusion:

Ultimately, the study display new avenues for the clinical study and development of future therapeutics for AR. The ex vivo findings suggest the presence of higher AT2R in inflamed cells and the in-vitro results indicate that the agonism of these receptors reduces pro-inflammatory factors. The results provide a novel pathway to treat rheumatoid arthritis that can be used as an alternative or addition to current AR therapeutic drugs such as NSAIDs, steroids DMARDs and other biological agents.

Clinical perspective:

• Few, if not any, studies have evaluated the association or AT2R and RA, as well as the efficacy of an AT2R agonist in its treatment.
• The study by Terenzi et al. demonstrates the effectiveness of AT2R agonists in reducing the inflammatory response that is associated with rheumatoid arthritis.

References:

• Claudia, C., Donatella, L., Katia, C., and Ornella, M. (2013). Optimization of �in vitro� culture conditions for human arthritis rheumatoid synovial fibroblasts. Frontiers In Immunology 4:.
• Macías-Segura, N., Castañeda-Delgado, J., Bastian, Y., Santiago-Algarra, D., Castillo-Ortiz, J., and Alemán-Navarro, A. et al. (2018). Transcriptional signature associated with early rheumatoid arthritis and healthy individuals at high risk to develop the disease. PLOS ONE 13: e0194205.
• Marino, F., Maresca, A., Cosentino, M., Castiglioni, L., Rasini, E., and Mongiardi, C. et al. (2012). Angiotensin II type 1 and type 2 receptor expression in circulating monocytes of diabetic and hypercholesterolemic patients over 3-month rosuvastatin treatment. Cardiovascular Diabetology 11: 153.
• Ruiz-Ortega, M., Lorenzo, Ó., Rupérez, M., Blanco, J., and Egido, J. (2001). Systemic Infusion of Angiotensin II into Normal Rats Activates Nuclear Factor-κB and AP-1 in the Kidney. The American Journal Of Pathology 158: 1743-1756.
• Sampson, A., Irvine, J., Shihata, W., Dragoljevic, D., Lumsden, N., and Huet, O. et al. (2015). Compound 21, a selective agonist of angiotensin AT2receptors, prevents endothelial inflammation and leukocyte adhesionin vitroandin vivo. British Journal Of Pharmacology 173: 729-740.
• Terenzi, R., Manetti, M., Rosa, I., Romano, E., Galluccio, F., and Guiducci, S. et al. (2017). Angiotensin II type 2 receptor (AT2R) as a novel modulator of inflammation in rheumatoid arthritis synovium. Scientific Reports 7:.
• Toledano, E., García de Yébenes, M., González-Álvaro, I., and Carmona, L. (2019). Severity Indices in Rheumatoid Arthritis: A Systematic Review. Reumatología Clínica (English Edition) 15: 146-151.
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• Wang, Y., Kou, J., Zhang, H., Wang, C., Li, H., and Ren, Y. et al. (2018). The renin-angiotensin system in the synovium promotes periarticular osteopenia in a rat model of collagen-induced arthritis. International Immunopharmacology 65: 550-558.
• Wang, Y., Liu, Y., Xi, Z., Yu, Y., Liu, L., and Mao, J. et al. (2019). A multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of Huangqi Guizhi Wuwutang granule in patients with rheumatoid arthritis. Medicine 98: e14888.