A systems approach identifies HIPK2 as a key regulator of kidney fibrosis

被引:138
作者
Jin, Yuanmeng [1 ,2 ]
Ratnam, Krishna [1 ]
Chuang, Peter Y. [1 ]
Fan, Ying [1 ]
Zhong, Yifei [1 ]
Dai, Yan [1 ]
Mazloom, Amin R. [3 ,4 ]
Chen, Edward Y. [3 ,4 ]
D'Agati, Vivette [5 ]
Xiong, Huabao [6 ]
Ross, Michael J. [1 ]
Chen, Nan [2 ]
Ma'ayan, Avi [3 ,4 ]
He, John Cijiang [1 ,3 ,7 ]
机构
[1] Mt Sinai Sch Med, Dept Med, Div Nephrol, New York, NY 10029 USA
[2] Jiao Tong Univ Sch Med, Ruijin Hosp, Dept Nephrol, Shanghai, Peoples R China
[3] Mt Sinai Sch Med, Dept Pharmacol & Syst Therapeut, New York, NY USA
[4] SBCNY, New York, NY USA
[5] Columbia Univ, Dept Pathol, New York, NY USA
[6] Mt Sinai Sch Med, Immunobiol Ctr, New York, NY USA
[7] James J Peters Vet Adm Med Ctr, New York, NY USA
基金
美国国家卫生研究院;
关键词
EPITHELIAL-MESENCHYMAL TRANSITION; HIV-ASSOCIATED NEPHROPATHY; DNA-DAMAGE RESPONSE; TGF-BETA; INTERSTITIAL FIBROSIS; N-ACETYLCYSTEINE; APOPTOSIS; TRANSCRIPTION; ACTIVATION; GROWTH;
D O I
10.1038/nm.2685
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
Kidney fibrosis is a common process that leads to the progression of various types of kidney disease. We used an integrated computational and experimental systems biology approach to identify protein kinases that regulate gene expression changes in the kidneys of human immunodeficiency virus (HIV) transgenic mice (Tg26 mice), which have both tubulointerstitial fibrosis and glomerulosclerosis. We identified homeo-domain interacting protein kinase 2 (HIPK2) as a key regulator of kidney fibrosis. HIPK2 was upregulated in the kidneys of Tg26 mice and in those of patients with various kidney diseases. HIV infection increased the protein concentrations of HIPK2 by promoting oxidative stress, which inhibited the seven in absentia homolog 1 (SIAH1)-mediated proteasomal degradation of HIPK2. HIPK2 induced apoptosis and the expression of epithelial-to-mesenchymal transition markers in kidney epithelial cells by activating the p53, transforming growth factor beta (TGF-beta)-SMAD family member 3 (Smad3) and Wnt-Notch pathways. Knockout of HIPK2 improved renal function and attenuated proteinuria and kidney fibrosis in Tg26 mice, as well as in other murine models of kidney fibrosis. We therefore conclude that HIPK2 is a potential target for anti-fibrosis therapy.
引用
收藏
页码:580 / 588
页数:9
相关论文
共 56 条
[1]
Genes2Networks: connecting lists of gene symbols using mammalian protein interactions databases [J].
Berger, Seth I. ;
Posner, Jeremy M. ;
Ma'ayan, Avi .
BMC BIOINFORMATICS, 2007, 8 (1)
[2]
Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans [J].
Bielesz, Bernhard ;
Sirin, Yasemin ;
Si, Han ;
Niranjan, Thiruvur ;
Gruenwald, Antje ;
Ahn, Seonho ;
Kato, Hideki ;
Pullman, James ;
Gessler, Manfred ;
Haase, Volker H. ;
Susztak, Katalin .
JOURNAL OF CLINICAL INVESTIGATION, 2010, 120 (11) :4040-4054
[3]
Snail activation disrupts tissue homeostasis and induces fibrosis in the adult kidney [J].
Boutet, Agnes ;
De Frutos, Cristina A. ;
Maxwell, Patrick H. ;
Mayol, M. Jose ;
Romero, J. ;
Nieto, M. Angela .
EMBO JOURNAL, 2006, 25 (23) :5603-5613
[4]
Bruggeman LA, 2000, J AM SOC NEPHROL, V11, P2079, DOI 10.1681/ASN.V11112079
[5]
HIPK2 - a versatile switchboard regulating the transcription machinery and cell death [J].
Calzado, Marco A. ;
Renner, Florian ;
Roscic, Ana ;
Schmitz, M. Lienhard .
CELL CYCLE, 2007, 6 (02) :139-143
[6]
[7]
Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis [J].
D'Orazi, G ;
Cecchinelli, B ;
Bruno, T ;
Manni, I ;
Higashimoto, Y ;
Saito, S ;
Gostissa, M ;
Coen, S ;
Marchetti, A ;
Del Sal, G ;
Piaggio, G ;
Fanciulli, M ;
Appella, E ;
Soddu, S .
NATURE CELL BIOLOGY, 2002, 4 (01) :11-19
[8]
HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function [J].
Di Stefano, V ;
Blandino, G ;
Sacchi, A ;
Soddu, S ;
D'Orazi, G .
ONCOGENE, 2004, 23 (30) :5185-5192
[9]
HIV-ASSOCIATED NEPHROPATHY IN TRANSGENIC MICE EXPRESSING HIV-1 GENES [J].
DICKIE, P ;
FELSER, J ;
ECKHAUS, M ;
BRYANT, J ;
SILVER, J ;
MARINOS, N ;
NOTKINS, AL .
VIROLOGY, 1991, 185 (01) :109-119
[10]
Evidence that inhibition of tubular cell apoptosis protects against renal damage and development of fibrosis following ureteric obstruction [J].
Docherty, NG ;
O'Sullivan, OE ;
Healy, DA ;
Fitzpatrick, JM ;
Watson, RWG .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2006, 290 (01) :F4-F13