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Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury.

ABSTRACT: Interstitial fibrosis is an important contributor to graft loss in chronic renal allograft injury. Inflammatory macrophages are associated with fibrosis in renal allografts, but how these cells contribute to this damaging response is not clearly understood. Here, we investigated the role of macrophage-to-myofibroblast transition in interstitial fibrosis in human and experimental chronic renal allograft injury. In biopsy specimens from patients with active chronic allograft rejection, we identified cells undergoing macrophage-to-myofibroblast transition by the coexpression of macrophage (CD68) and myofibroblast (?-smooth muscle actin [?-SMA]) markers. CD68⁺/?-SMA⁺ cells accounted for approximately 50% of the myofibroblast population, and the number of these cells correlated with allograft function and the severity of interstitial fibrosis. Similarly, in C57BL/6J mice with a BALB/c renal allograft, cells coexpressing macrophage markers (CD68 or F4/80) and ?-SMA composed a significant population in the interstitium of allografts undergoing chronic rejection. Fate-mapping in Lyz2-Cre/Rosa26-Tomato mice showed that approximately half of ?-SMA⁺ myofibroblasts in renal allografts originated from recipient bone marrow-derived macrophages. Knockout of Smad3 protected against interstitial fibrosis in renal allografts and substantially reduced the number of macrophage-to-myofibroblast transition cells. Furthermore, the majority of macrophage-to-myofibroblast transition cells in human and experimental renal allograft rejection coexpressed the M2-type macrophage marker CD206, and this expression was considerably reduced in Smad3-knockout recipients. In conclusion, our studies indicate that macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury. Moreover, the transition of bone marrow-derived M2-type macrophages to myofibroblasts in the renal allograft is regulated via a Smad3-dependent mechanism.

SUBMITTER: Wang YY

PROVIDER: S-EPMC5491278 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury.

Wang Ying-Ying YY Jiang Hong H Pan Jun J Huang Xiao-Ru XR Wang Yu-Cheng YC Huang Hong-Feng HF To Ka-Fai KF Nikolic-Paterson David J DJ Lan Hui-Yao HY Chen Jiang-Hua JH

Journal of the American Society of Nephrology : JASN 20170216 7

Interstitial fibrosis is an important contributor to graft loss in chronic renal allograft injury. Inflammatory macrophages are associated with fibrosis in renal allografts, but how these cells contribute to this damaging response is not clearly understood. Here, we investigated the role of macrophage-to-myofibroblast transition in interstitial fibrosis in human and experimental chronic renal allograft injury. In biopsy specimens from patients with active chronic allograft rejection, we identifi ...[more]

PMID: 28209809

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Project description:Chronic allograft dysfunction (CAD) is a major factor that hinders kidney transplant survival in the long run. Epithelial-mesenchymal transition (EMT) has been confirmed to significantly contribute to interstitial fibrosis/tubular atrophy (IF/TA), which is the main histopathological feature of CAD. Aberrant expression of the regulator of calcineurin 1 (RCAN1), recognized as an endogenous inhibitor of the calcineurin phosphatase, has been shown to be extensively involved in various kidney diseases. However, it remains unclear how RCAN1.4 regulates IF/TA formation in CAD patients. Herein, an in vivo mouse renal transplantation model and an in vitro model of human renal tubular epithelial cells (HK-2) treated with tumor necrosis factor-α (TNF-α) were employed. Our results proved that RCAN1.4 expression was decreased in vivo and in vitro, in addition to the up-regulation of Yin Yang 1 (YY1), a transcription factor that has been reported to convey multiple functions in chronic kidney disease (CKD). Knocking in of RCAN1.4 efficiently attenuated chronic renal allograft interstitial fibrosis in vivo and inhibited TNF-α-induced EMT in vitro through regulating anti-oxidative stress and the calcineurin/nuclear factor of activated T cells cytoplasmic 1 (NFATc1) signaling pathway. In addition, suppression of YY1 mediated by shRNA or siRNA alleviated TNF-α-induced EMT through abolishing reactive species partly in an RCAN1.4-dependent manner. Notably, we confirmed that YY1 negatively regulated RCAN1.4 transcription by directly interacting with the RCAN1.4 promoter. In addition, histone deacetylase 2 (HDAC2) interacted with YY1 to form a multi-molecular complex, which was involved in TNF-α-induced RCAN1.4 transcriptional repression. Therefore, RCAN1.4 is suggested to be modulated by the YY1/HDAC2 transcription repressor complex in an epigenetic manner, which is a mediated nephroprotective effect partly through modulating O2⋅- generation and the calcineurin/NFATc1 signaling pathway. Thus, the YY1-RCAN1.4 axis constitutes an innovative target for IF/TA treatment in CAD patients.

Dataset Information

Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury.

Publications

Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury.

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