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Soluble guanylyl cyclase (sGC) catalyses synthesis of cGMP in response to NO. cGMP\u2010amplifying agents, including NO donors and phosphodiesterase 9 inhibitors, alleviate TNF\u03b1\u2010induced inflammation in wild\u2010type C57BL\/6 mice and in \u2018humanised\u2019 mouse models of SCD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Effects of the sGC stimulator olinciguat on intravascular inflammation and renal injury were studied in acute (C57BL6 and Berkeley mice) and chronic (Townes mice) mouse models of TNF\u03b1\u2010induced and systemic inflammation associated with SCD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Acute treatment with olinciguat attenuated increases in plasma biomarkers of endothelial cell activation and leukocyte\u2010endothelial cell interactions in TNF\u03b1\u2010challenged mice. Co\u2010treatment with hydroxyurea, an FDA\u2010approved SCD therapeutic agent, further augmented the anti\u2010inflammatory effect of olinciguat. In the Berkeley mouse model of TNF\u03b1\u2010induced vaso\u2010occlusive crisis, a single dose of olinciguat attenuated leukocyte\u2010endothelial cell interactions, improved blood flow and prolonged survival time compared to vehicle\u2010treated mice. In Townes SCD mice, plasma biomarkers of inflammation and endothelial cell activation were lower in olinciguat\u2010 than in vehicle\u2010treated mice. In addition, kidney mass, water consumption, 24\u2010h urine excretion, plasma levels of cystatin C and urinary excretion of N\u2010acetyl\u2010\u03b2\u2010d\u2010glucosaminidase and neutrophil gelatinase\u2010associated lipocalin were lower in Townes mice treated with olinciguat than in vehicle\u2010treated mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Our results suggest that the sGC stimulator olinciguat attenuates inflammation, vaso\u2010occlusion and kidney injury in mouse models of SCD and systemic inflammation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15492","type":"journal-article","created":{"date-parts":[[2021,4,17]],"date-time":"2021-04-17T10:10:40Z","timestamp":1618654240000},"page":"3463-3475","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Olinciguat, a stimulator of soluble guanylyl cyclase, attenuates inflammation, vaso\u2010occlusion and nephropathy in mouse models of sickle cell disease"],"prefix":"10.1111","volume":"178","author":[{"given":"Boris","family":"Tchernychev","sequence":"first","affiliation":[{"name":"Cyclerion Therapeutics Inc. 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