A potent truncated form of human soluble CR1 is protective in a mouse model of renal ischemia–reperfusion injury

Abstract The complement system is a potent mediator of ischemia–reperfusion injury (IRI), which detrimentally affects the function and survival of transplanted kidneys. Human complement receptor 1 (HuCR1) is an integral membrane protein that inhibits complement activation by blocking the convertases...

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Autores principales:	Anjan K. Bongoni, Ingela B. Vikstrom, Jennifer L. McRae, Evelyn J. Salvaris, Nella Fisicaro, Martin J. Pearse, Sandra Wymann, Tony Rowe, Adriana Baz Morelli, Matthew P. Hardy, Peter J. Cowan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6759be9e51d64710ba80a5394b27e1b6
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spelling	oai:doaj.org-article:6759be9e51d64710ba80a5394b27e1b62021-11-14T12:18:52ZA potent truncated form of human soluble CR1 is protective in a mouse model of renal ischemia–reperfusion injury10.1038/s41598-021-01423-y2045-2322https://doaj.org/article/6759be9e51d64710ba80a5394b27e1b62021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01423-yhttps://doaj.org/toc/2045-2322Abstract The complement system is a potent mediator of ischemia–reperfusion injury (IRI), which detrimentally affects the function and survival of transplanted kidneys. Human complement receptor 1 (HuCR1) is an integral membrane protein that inhibits complement activation by blocking the convertases that activate C3 and C5. We have previously reported that CSL040, a truncated form of recombinant soluble HuCR1 (sHuCR1), has enhanced complement inhibitory activity and improved pharmacokinetic properties compared to the parent molecule. Here, we compared the capacity of CSL040 and full-length sHuCR1 to suppress complement-mediated organ damage in a mouse model of warm renal IRI. Mice were treated with two doses of CSL040 or sHuCR1, given 1 h prior to 22 min unilateral renal ischemia and again 3 h later. 24 h after reperfusion, mice treated with CSL040 were protected against warm renal IRI in a dose-dependent manner, with the highest dose of 60 mg/kg significantly reducing renal dysfunction, tubular injury, complement activation, endothelial damage, and leukocyte infiltration. In contrast, treatment with sHuCR1 at a molar equivalent dose to 60 mg/kg CSL040 did not confer significant protection. Our results identify CSL040 as a promising therapeutic candidate to attenuate renal IRI and demonstrate its superior efficacy over full-length sHuCR1 in vivo.Anjan K. BongoniIngela B. VikstromJennifer L. McRaeEvelyn J. SalvarisNella FisicaroMartin J. PearseSandra WymannTony RoweAdriana Baz MorelliMatthew P. HardyPeter J. CowanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anjan K. Bongoni Ingela B. Vikstrom Jennifer L. McRae Evelyn J. Salvaris Nella Fisicaro Martin J. Pearse Sandra Wymann Tony Rowe Adriana Baz Morelli Matthew P. Hardy Peter J. Cowan A potent truncated form of human soluble CR1 is protective in a mouse model of renal ischemia–reperfusion injury
description	Abstract The complement system is a potent mediator of ischemia–reperfusion injury (IRI), which detrimentally affects the function and survival of transplanted kidneys. Human complement receptor 1 (HuCR1) is an integral membrane protein that inhibits complement activation by blocking the convertases that activate C3 and C5. We have previously reported that CSL040, a truncated form of recombinant soluble HuCR1 (sHuCR1), has enhanced complement inhibitory activity and improved pharmacokinetic properties compared to the parent molecule. Here, we compared the capacity of CSL040 and full-length sHuCR1 to suppress complement-mediated organ damage in a mouse model of warm renal IRI. Mice were treated with two doses of CSL040 or sHuCR1, given 1 h prior to 22 min unilateral renal ischemia and again 3 h later. 24 h after reperfusion, mice treated with CSL040 were protected against warm renal IRI in a dose-dependent manner, with the highest dose of 60 mg/kg significantly reducing renal dysfunction, tubular injury, complement activation, endothelial damage, and leukocyte infiltration. In contrast, treatment with sHuCR1 at a molar equivalent dose to 60 mg/kg CSL040 did not confer significant protection. Our results identify CSL040 as a promising therapeutic candidate to attenuate renal IRI and demonstrate its superior efficacy over full-length sHuCR1 in vivo.
format	article
author	Anjan K. Bongoni Ingela B. Vikstrom Jennifer L. McRae Evelyn J. Salvaris Nella Fisicaro Martin J. Pearse Sandra Wymann Tony Rowe Adriana Baz Morelli Matthew P. Hardy Peter J. Cowan
author_facet	Anjan K. Bongoni Ingela B. Vikstrom Jennifer L. McRae Evelyn J. Salvaris Nella Fisicaro Martin J. Pearse Sandra Wymann Tony Rowe Adriana Baz Morelli Matthew P. Hardy Peter J. Cowan
author_sort	Anjan K. Bongoni
title	A potent truncated form of human soluble CR1 is protective in a mouse model of renal ischemia–reperfusion injury
title_short	A potent truncated form of human soluble CR1 is protective in a mouse model of renal ischemia–reperfusion injury
title_full	A potent truncated form of human soluble CR1 is protective in a mouse model of renal ischemia–reperfusion injury
title_fullStr	A potent truncated form of human soluble CR1 is protective in a mouse model of renal ischemia–reperfusion injury
title_full_unstemmed	A potent truncated form of human soluble CR1 is protective in a mouse model of renal ischemia–reperfusion injury
title_sort	potent truncated form of human soluble cr1 is protective in a mouse model of renal ischemia–reperfusion injury
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6759be9e51d64710ba80a5394b27e1b6
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A potent truncated form of human soluble CR1 is protective in a mouse model of renal ischemia–reperfusion injury

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