Integrin β8 prevents pericyte-myofibroblast transition and renal fibrosis through inhibiting the TGF-β1/TGFBR1/Smad3 pathway in diabetic kidney disease

被引：10

作者：

Cao, Yiling ^{[1
]}

Su, Hua ^{[1
]}

Zeng, Jieyu ^{[1
]}

Xie, Yaru ^{[1
]}

Liu, Zezhou ^{[1
]}

Liu, Feng ^{[1
]}

Qiu, Yang ^{[1
]}

Yi, Fan ^{[2
]}

Lin, Jihong ^{[3
]}

Hammes, Hans -Peter ^{[3
]}

Zhang, Chun ^{[1
]}

机构：

[1] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Nephrol, Wuhan 430022, Peoples R China

[2] Shandong Univ, Sch Basic Med Sci, Dept Pharmacol, Jinan 250012, Peoples R China

[3] Heidelberg Univ, Med Fac Mannheim, Med Dept 5, D-68167 Mannheim, Germany

来源：

TRANSLATIONAL RESEARCH | 2024年 / 265卷

基金：

中国国家自然科学基金;

关键词：

Diabetic kidney disease; Pericyte; Fibrosis; Integrin beta 8; TGF-beta; 1; MESANGIAL CELL; TUBULOINTERSTITIAL FIBROSIS; FIBROBLAST ACTIVATION; TGF-BETA; MDM2; MECHANISMS; EXPRESSION; GROWTH;

D O I：

10.1016/j.trsl.2023.10.007

中图分类号：

R446 [实验室诊断]; R-33 [实验医学、医学实验];

学科分类号：

1001 ;

摘要：

Diabetic kidney disease (DKD) is one of the leading causes to develop end-stage kidney disease worldwide. Pericytes are implicated in the development of tissue fibrosis. However, the underlying mechanisms of pericytes in DKD remain largely unknown. We isolated and cultured primary pericytes and rat mesangial cells (HBZY-1). Western blot and qRT-PCR analysis were used to explore the role and regulatory mechanism of Integrin beta 8/transforming growth factor beta 1 (TGF-beta 1) pathway. We also constructed pericyte-specific Integrin beta 8 knock-in mice as the research objects to determine the role of Integrin beta 8 in vivo. We discovered that reduced Integrin beta 8 expression was closely associated with pericyte transition in DKD. Overexpressed Integrin beta 8 in pericytes dramatically suppressed TGF-beta 1/TGF beta receptor 1 (TGFBR1)/Smad3 signaling pathway and protected glomerular endothelial cells (GECs) in vitro. In vivo, pericyte-specific Integrin beta 8 knock-in ameliorated pericyte transition, endothelium injury and renal fibrosis in STZ-induced diabetic mice. Mechanistically, Murine double minute 2 (MDM2) was found to increase the degradation of Integrin beta 8 and caused TGF-beta 1 release and activation. Knockdown MDM2 could partly reverse the decline of Integrin beta 8 and suppress pericytes transition. In conclusion, the present findings suggested that upregulated MDM2 expression contributes to the degradation of Integrin beta 8 and activation of TGF-beta 1/TGFBR1/Smad3 signaling pathway, which ultimately leads to pericyte transition during DKD progression. These results indicate MDM2/Integrin beta 8 might be considered as therapeutic targets for DKD.

引用

页码：36 / 50

页数：15

共 51 条

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Ziyadeh, FN .

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