Managing renal fibrosis is challenging owing to the complex cell signaling redundancy in diseased kidneys.Renal fibrosis involves an immune response dominated by macrophages,which activates myofibroblasts in fibrotic ...Managing renal fibrosis is challenging owing to the complex cell signaling redundancy in diseased kidneys.Renal fibrosis involves an immune response dominated by macrophages,which activates myofibroblasts in fibrotic niches.However,macrophages exhibit high heterogeneity,hindering their potential as therapeutic cell targets.Herein,we aimed to eliminate specific macrophage subsets that drive the profibrotic immune response in the kidney both temporally and spatially.We identified the major profibrotic macrophage subset(Fn1+Spp1+Arg1+)in the kidney and then constructed a 12-mer glycopeptide that was designated as bioactivated in vivo assembly PK(BIVA-PK)to deplete these cells.BIVA-PK specifically binds to and is internalized by profibrotic macrophages.By inducing macrophage cell death,BIVA-PK reshaped the renal microenvironment and suppressed profibrotic immune responses.The robust efficacy of BIVA-PK in ameliorating renal fibrosis and preserving kidney function highlights the value of targeting macrophage subsets as a potential therapy for patients with CKD.展开更多
基金National Natural Science Foundation of China(grant numbers 82000657 to QO,82030025,32141005 to XC and E3041101 to LL)National Key R&D Program of China(grant number 2021YFC3002203 to LZ).
文摘Managing renal fibrosis is challenging owing to the complex cell signaling redundancy in diseased kidneys.Renal fibrosis involves an immune response dominated by macrophages,which activates myofibroblasts in fibrotic niches.However,macrophages exhibit high heterogeneity,hindering their potential as therapeutic cell targets.Herein,we aimed to eliminate specific macrophage subsets that drive the profibrotic immune response in the kidney both temporally and spatially.We identified the major profibrotic macrophage subset(Fn1+Spp1+Arg1+)in the kidney and then constructed a 12-mer glycopeptide that was designated as bioactivated in vivo assembly PK(BIVA-PK)to deplete these cells.BIVA-PK specifically binds to and is internalized by profibrotic macrophages.By inducing macrophage cell death,BIVA-PK reshaped the renal microenvironment and suppressed profibrotic immune responses.The robust efficacy of BIVA-PK in ameliorating renal fibrosis and preserving kidney function highlights the value of targeting macrophage subsets as a potential therapy for patients with CKD.
