Second Generation I-Body AD-214 Attenuates Unilateral Ureteral Obstruction (UUO)-Induced Kidney Fibrosis Through Inhibiting Leukocyte Infiltration and Macrophage Migration.

Qinghua Cao, Michael Foley, Anthony J Gill, Angela Chou, Xin-Ming Chen, Carol A Pollock

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Article in International journal of molecular sciences, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

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6 authors.

Qinghua CaoRenal Medicine, Kolling Institute of Medical Research, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.ORCID 0000-0002-8123-3097

Michael FoleyThe Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.ORCID 0000-0003-1349-4698

Anthony J GillDepartment of Anatomical Pathology, NSW Health Pathology, Royal North Shore Hospital, Sydney, NSW 2065, Australia.

Angela ChouDepartment of Anatomical Pathology, NSW Health Pathology, Royal North Shore Hospital, Sydney, NSW 2065, Australia.

Xin-Ming ChenRenal Medicine, Kolling Institute of Medical Research, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.

Carol A PollockRenal Medicine, Kolling Institute of Medical Research, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.

Funding

National Health and Medical Research Council (NHMRC) 2019818

6 · The paper itself

Abstract

Kidney fibrosis is the common pathological pathway in progressive chronic kidney disease (CKD), and current treatments are largely ineffective. The C-X-C chemokine receptor 4 (CXCR4) is crucial to fibrosis development. By using neural cell adhesion molecules as scaffolds with binding loops that mimic the shape of shark antibodies, fully humanized single-domain i-bodies have been developed. The first-generation i-body, AD-114, demonstrated antifibrotic effects in a mouse model of folic acid (FA)-induced renal fibrosis. The second-generation i-body, AD-214, is an Fc-fusion protein with an extended half-life, enhanced activity, and a mutated Fc domain to prevent immune activation. To investigate the renoprotective mechanisms of AD-214, RPTEC/TERT1 cells (a human proximal tubular cell line) were incubated with TGF-b1 with/without AD-214 and the supernatant was collected to measure collagen levels by Western blot. Mice with unilateral ureteral obstruction (UUO) received AD-214 intraperitoneally (i.p.) every two days for 14 days. Kidney fibrosis markers and kidney function were then analyzed. AD-214 suppressed TGF-b1-induced collagen overexpression in RPTEC/TERT1 cells. In UUO mice, AD-214 reduced extracellular matrix (ECM) deposition, restored kidney function, and limited leukocyte infiltration. In a scratch assay, AD-214 also inhibited macrophage migration. To conclude, i-body AD-214 attenuates UUO-induced kidney fibrosis by inhibiting leukocyte infiltration and macrophage migration.

Indexed as

FibrosisMacrophagesUreteral ObstructionAnimalsCell LineCell MovementDisease Models, AnimalHumansKidneyKidney DiseasesLeukocytesMaleMiceMice, Inbred C57BLReceptors, CXCR4Transforming Growth Factor beta1Receptors, CXCR4Transforming Growth Factor beta1AD-214CXCR4i-bodykidney fibrosismacrophage

Identifiers

PMID39684834

DOI10.3390/ijms252313127

PMCPMC11641963

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