Abstract
Background
There is a growing search for therapeutic targets in the treatment of gout. The present study aimed to evaluate the analgesic and anti-inflammatory potential of angiotensin type 2 receptor (AT2R) antagonism in an acute gout attack mouse model.
Methods
Male wild-type (WT) C57BL/6 mice either with the AT2R antagonist, PD123319 (10 pmol/joint), or with vehicle injections, or AT2R KO mice, received intra-articular (IA) injection of monosodium urate (MSU) crystals (100 µg/joint), that induce the acute gout attack, and were tested for mechanical allodynia, thermal hyperalgesia, spontaneous nociception and ankle edema development at several times after the injections. To test an involvement of AT2R in joint pain, mice received an IA administration of angiotensin II (0.05–5 nmol/joint) with or without PD123319, and were also evaluated for pain and edema development. Ankle joint tissue samples from mice undergoing the above treatments were assessed for myeloperoxidase activity, IL-1β release, mRNA expression analyses and nitrite/nitrate levels, 4 h after injections.
Results
AT2R antagonism has robust antinociceptive effects on mechanical allodynia (44% reduction) and spontaneous nociception (56%), as well as anti-inflammatory effects preventing edema formation (45%), reducing myeloperoxidase activity (54%) and IL-1β levels (32%). Additionally, Agtr2tm1a mutant mice have largely reduced painful signs of gout. Angiotensin II administration causes pain and inflammation, which was prevented by AT2R antagonism, as observed in mechanical allodynia 4 h (100%), spontaneous nociception (46%), cold nociceptive response (54%), edema formation (83%), myeloperoxidase activity (48%), and IL-1β levels (89%). PD123319 treatment also reduces NO concentrations (74%) and AT2R mRNA levels in comparison with MSU untreated mice.
Conclusion
Our findings show that AT2R activation contributes to acute pain in experimental mouse models of gout. Therefore, the antagonism of AT2R may be a potential therapeutic option to manage gout arthritis.
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Data availability
The data that support the findings of this study are available on request from the corresponding author Silva C. R. The data are not publicly available due to the inexistence of free repositories where we can do that in a safe way.
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Acknowledgements
The authors would like to thank Pró-Reitoria de Pesquisa e Pós-graduação da Universidade Federal de Uberlândia (PROPP-UFU) and Rede de Biotérios da Universidade Federal de Uberlândia (REBIR-UFU) by animal supply, infrastructure and services provided. We also thank for technical support from Marina de Souza Lima, Sebastiana Abadia Inácio and Luciana Machado Bastos.
Funding
This study was supported by grants from the Brazilian National Council for Scientific and Technological Development (CNPq). The fellowships from CNPq, Higher Education Personnel Improvement Coordination (CAPES) and Foundation for Research Support of the State of Minas Gerais (FAPEMIG) are also acknowledged.
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SCR and VTN were involved in the study conception, experimental data confection, statistical analyses and writing procedure. SALL, GRM, MJPL, CTM and CJJP helped with all molecular analyses; PLG and MN performed the knockout management and experiments and final writing corrections; ÁVMR, GLR and FJ helped with reagents, equipment’s, and the study conception. All authors read and contributed to the final writing of the manuscript and are in accordance with the publication.
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Vieira, T.N., Saraiva, A.L.L., Guimarães, R.M. et al. Angiotensin type 2 receptor antagonism as a new target to manage gout. Inflammopharmacol 30, 2399–2410 (2022). https://doi.org/10.1007/s10787-022-01076-x
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DOI: https://doi.org/10.1007/s10787-022-01076-x