Kindlin-2 Acts as a Key Mediator of Lung Fibroblast Activation and Pulmonary Fibrosis Progression

Zhang，Ping1; Wang，Jiaxin1; Luo，Weiren2; Yuan，Jifan1; Cui，Chunhong1; Guo，Ling1; Wu，Chuanyue3

2021-07-01

10.1165/rcmb.2020-0320OC

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY   影响因子和分区

1044-1549

1535-4989

Pulmonary fibrosis is a progressive and fatal lung disease characterized by activation of lung fibroblasts and excessive deposition of collagen matrix. We show here that the concentrations of kindlin-2 and its binding partner PYCR1, a key enzyme for proline synthesis, are significantly increased in the lung tissues of human patients with pulmonary fibrosis. Treatment of human lung fibroblasts with TGF-b1 markedly increased the expression of kindlin-2 and PYCR1, resulting in increased kindlin-2 mitochondrial translocation, formation of the kindlin-2–PYCR1 complex, and proline synthesis. The concentrations of the kindlin-2–PYCR1 complex and proline synthesis were markedly reduced in response to pirfenidone or nintedanib, two clinically approved therapeutic drugs for pulmonary fibrosis. Furthermore, depletion of kindlin-2 alone was sufficient to suppress TGF-b1–induced increases of PYCR1 expression, proline synthesis, and fibroblast activation. Finally, using a bleomycin mouse model of pulmonary fibrosis, we show that ablation of kindlin-2 effectively reduced the concentrations of PYCR1, proline, and collagen matrix and alleviate the progression of pulmonary fibrosis in vivo. Our results suggest that kindlin-2 is a key promoter of lung fibroblast activation, collagen matrix synthesis, and pulmonary fibrosis, underscoring the therapeutic potential of targeting the kindlin-2 signaling pathway for control of this deadly lung disease.

Kindlin-2 Proline synthesis Pulmonary fibrosis PYCR1 TGF-b1

SCI

英语

第一

WOS:000672720800010

BIOLOGY & BIOCHEMISTRY

2-s2.0-85110384131

Scopus

1.Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Shenzhen Key Laboratory of Cell Microenvironment,Academy for Advanced Interdisciplinary Studies and Department of Biology,Southern University of Science and Technology,Shenzhen,China
2.Department of Pathology,Cancer Research Institute,The Second Affiliated Hospital of Southern University of Science and Technology,Shenzhen Third People’s Hospital,National Clinical Research Center for Infectious Diseases,Shenzhen,China
3.Department of Pathology,University of Pittsburgh School of Medicine,Pittsburgh,United States

Zhang，Ping,Wang，Jiaxin,Luo，Weiren,et al. Kindlin-2 Acts as a Key Mediator of Lung Fibroblast Activation and Pulmonary Fibrosis Progression[J]. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY,2021,65(1):54-69.

Zhang，Ping.,Wang，Jiaxin.,Luo，Weiren.,Yuan，Jifan.,Cui，Chunhong.,...&Wu，Chuanyue.(2021).Kindlin-2 Acts as a Key Mediator of Lung Fibroblast Activation and Pulmonary Fibrosis Progression.AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY,65(1),54-69.

Zhang，Ping,et al."Kindlin-2 Acts as a Key Mediator of Lung Fibroblast Activation and Pulmonary Fibrosis Progression".AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 65.1(2021):54-69.