Circulating Bone Morphogenetic Protein 1-3 Isoform Increases Renal Fibrosis

被引:49
作者
Grgurevic, Lovorka [1 ]
Macek, Boris [2 ]
Healy, David R. [3 ]
Brault, Amy L. [3 ]
Erjavec, Igor [1 ]
Cipcic, Antonio [1 ]
Grgurevic, Ivica [4 ]
Rogic, Dunja [5 ]
Galesic, Kresimir [4 ]
Brkljacic, Jelena [1 ]
Stern-Padovan, Ranka [6 ]
Paralkar, Vishwas M. [3 ]
Vukicevic, Slobodan [1 ]
机构
[1] Univ Zagreb, Lab Mineralized Tissues, Sch Med, Ctr Translat & Clin Res, Zagreb 10000, Croatia
[2] Univ Tubingen, Proteome Ctr, Interdept Inst Cell Biol, Tubingen, Germany
[3] Pfizer Inc, Pfizer Res & Dev, Groton, CT 06340 USA
[4] Dubrava Univ Hosp, Dept Internal Med, Zagreb, Croatia
[5] Univ Hosp Ctr, Dept Lab Diag, Zagreb, Croatia
[6] Univ Hosp Ctr, Dept Diagnost & Intervent Radiol, Zagreb, Croatia
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2011年 / 22卷 / 04期
关键词
GROWTH-FACTOR-BETA; EXTRACELLULAR-MATRIX ACCUMULATION; HUMAN EMBRYONIC-DEVELOPMENT; TGF-BETA; EXPERIMENTAL GLOMERULONEPHRITIS; GENE-EXPRESSION; IN-VITRO; DECORIN; KIDNEY; RECEPTOR;
D O I
10.1681/ASN.2010070722
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Bone morphogenetic proteins (BMPs) participate in organ regeneration through autocrine and paracrine actions, but the existence and effects of these proteins in the systemic circulation is unknown. Using liquid chromatography mass spectrometry, we identified BMP6, GDF15, and the BMP1-3 isoform of the Bmp1 gene in plasma samples from healthy volunteers and patients with CKD. We isolated the endogenous BMP1-3 protein and demonstrated that it circulates as an active enzyme, evidenced by its ability to cleave dentin matrix protein-1 in vitro. In rats with CKD, administration of recombinant BMP1-3 increased renal fibrosis and reduced survival. In contrast, administration of a BMP1-3-neutralizing antibody reduced renal fibrosis, preserved renal function, and increased survival. In addition, treating with the neutralizing antibody was associated with low plasma levels of TGF beta 1 and connective tissue growth factor. In HEK293 cells and remnant kidneys, BMP1-3 increased the transcription of collagen type I, TGF beta 1, beta-catenin, and BMP7 via a BMP- and Wnt-independent mechanism that involved signaling through an integrin 01 subunit. The profibrotic effect of BMP1-3 may, in part, be a result of the accompanied decrease in decorin (DCN) expression. Taken together, inhibition of circulating BMP1-3 reduces renal fibrosis, suggesting that this pathway may be a therapeutic target for CKD.
引用
收藏
页码:681 / 692
页数:12
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