Cell division autoantigen 1 enhances signaling and the profibrotic effects of transforming growth factor-β in diabetic nephropathy

被引：28

作者：

Tu, Yugang ^{[1
]}

Wu, Tieqiao ^{[1
]}

Dai, Aozhi ^{[1
]}

Pham, Yen ^{[1
]}

Chew, Phyllis ^{[1
]}

de Haan, Judy B. ^{[1
]}

Wang, Yu ^{[1
]}

Toh, Ban-Hock ^{[2
]}

Zhu, Hongjian ^{[3
]}

Cao, Zemin ^{[1
]}

Cooper, Mark E. ^{[1
,4
]}

Chai, Zhonglin ^{[1
]}

机构：

[1] Baker IDI Heart & Diabet Inst, Diabet & Metab Div, Melbourne, Vic 3004, Australia

[2] Monash Univ, Autoimmun Lab, Dept Med, Ctr Inflammatory Dis, Clayton, Vic, Australia

[3] Univ Melbourne, Dept Surg RMH, Parkville, Vic 3052, Australia

[4] Monash Univ, Fac Med, Dept Immunol, Clayton, Vic, Australia

来源：

KIDNEY INTERNATIONAL | 2011年 / 79卷 / 02期

基金：

英国医学研究理事会;

关键词：

diabetic nephropathy; renal fibrosis; TGF-beta; GLYCATION END-PRODUCTS; 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-2; HUMAN MESANGIAL CELLS; ERK MAP KINASE; COLLAGEN EXPRESSION; ANGIOTENSIN-II; POTENTIAL ROLE; HUMAN LUNG; RECEPTOR; HYPERTENSION;

D O I：

10.1038/ki.2010.374

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：

Cell division autoantigen 1 (CDA1) modulates cell proliferation and transforming growth factor-beta (TGF-beta) signaling in a number of cellular systems; here we found that its levels were elevated in the kidneys of two animal models of diabetic renal disease. The localization of CDA1 to tubular cells and podocytes in human kidney sections was similar to that seen in the rodent models. CDA1 small interfering RNA knockdown markedly attenuated, whereas its overexpression increased TGF-beta signaling, modulating the expression of TGF-beta, TGF-beta receptors, connective tissue growth factor, collagen types I, Ill, IV, and fibronectin genes in HK-2 cells. CDA1 and TGF-beta together were synergistic in stimulating TGF-beta signaling and target gene expression. CDA1 knockdown effectively blocked TGF-beta-stimulated expression of collagen genes. This was due to its ability to modulate the TGF-beta type I, but not the type II, receptor, leading to increased phosphorylation of Smad3 and extracellular signal-regulated kinase mitogen-activated protein kinase. Furthermore, the Smad3 inhibitor, SIS3, markedly attenuated the activities of CDA1 in stimulating TGF-beta signaling as well as gene expression of collagens I, III, and IV. Thus, our in vitro and in vivo findings show that CDA1 has a critical role in TGF-beta signaling in the kidney. Kidney International (2011) 79, 199-209; doi:10.1038/ki.2010.374; published online 20 October 2010

引用

页码：199 / 209

页数：11