PDGFRA in vascular adventitial MSCs promotes neointima formation in arteriovenous fistula in chronic kidney disease
Ke Song, Ying Qing, Qunying Guo, Eric K. Peden, Changyi Chen, William E. Mitch, Luan Truong, Jizhong Cheng
Ke Song, Ying Qing, Qunying Guo, Eric K. Peden, Changyi Chen, William E. Mitch, Luan Truong, Jizhong Cheng
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Research Article Nephrology Stem cells

PDGFRA in vascular adventitial MSCs promotes neointima formation in arteriovenous fistula in chronic kidney disease

Abstract

Chronic kidney disease (CKD) induces the failure of arteriovenous fistulas (AVFs) and promotes the differentiation of vascular adventitial GLI1-positive mesenchymal stem cells (GMCs). However, the roles of GMCs in forming neointima in AVFs remain unknown. GMCs isolated from CKD mice showed increased potential capacity of differentiation into myofibroblast-like cells. Increased activation of expression of PDGFRA and hedgehog (HH) signaling were detected in adventitial cells of AVFs from patients with end-stage kidney disease and CKD mice. PDGFRA was translocated and accumulated in early endosome when sonic hedgehog was overexpressed. In endosome, PDGFRA-mediated activation of TGFB1/SMAD signaling promoted the differentiation of GMCs into myofibroblasts, extracellular matrix deposition, and vascular fibrosis. These responses resulted in neointima formation and AVF failure. KO of Pdgfra or inhibition of HH signaling in GMCs suppressed the differentiation of GMCs into myofibroblasts. In vivo, specific KO of Pdgfra inhibited GMC activation and vascular fibrosis, resulting in suppression of neointima formation and improvement of AVF patency despite CKD. Our findings could yield strategies for maintaining AVF functions.

Authors

Ke Song, Ying Qing, Qunying Guo, Eric K. Peden, Changyi Chen, William E. Mitch, Luan Truong, Jizhong Cheng

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Figure 8

Pdgfra KO in GMCs suppresses CKD-induced neointima formation in AVFs.

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Pdgfra KO in GMCs suppresses CKD-induced neointima formation in AVFs. (...
(A) The time course for creation of the CKD and AVF in WT (Gli1-CreERT2) and GMCPA–/– (Gli1-CreERT2/PDGFRAfl/fl) mice. (B) WT and GMCPA–/– mice were treated with tamoxifen or vehicle. The expression of PDGFRA and GLI1 in common carotid arteries and jugular veins was determined by immunostaining. Scale bars: 100 μm. (C and D) Representative Western blot (WB) and densitometric analysis of the expression of PDGFRA and myofibroblast markers in the arteries from WT and GMCPA–/– mice after tamoxifen treatment. Protein expression of PDGFRA was normalized to GAPDH and expressed as fold change of WT mice (D). Data were collected from 6 mice/group and presented as mean ± SEM. **P< 0.01 versus WT mice (t test). (E) Representative images of H&E staining of the AVFs created in WT and GMCPA–/– mice with or without CKD. Scale bars: 500 μm. (F) Quantification of the neointima area of AVFs created in WT and GMCPA–/– mice with or without CKD. Neointima area was expressed as fold change of WT/sham mouse. Data were collected from 7 mice/group and presented as mean ± SEM. **P < 0.01 versus WT/sham, ##P < 0.01 versus WT/CKD (1-way ANOVA). (G and H) Representative images of double immunofluorescent staining of α-SMA and COL3A1 of the AVFs created in WT and GMCPA–/– mice with or without CKD. Scale bars: 50 μm. Quantitative densitometry was normalized to DAPI area and expressed as fold change of WT/sham mouse (H). Data were collected from 7 mice/group and presented as mean ± SEM. **P < 0.01 versus WT/Sham, ##P < 0.01 versus WT/CKD (2-way ANOVA). GMCs, GLI1-positive mesenchymal stem cells; CKD, chronic kidney disease; AVFs, arteriovenous fistula; α-SMA, α-smooth muscle actin; COL3A1, collagen type III α 1.