Abstract
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 β (TGF-β)-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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Apoptosis / genetics
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Carrier Proteins / metabolism*
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Cell Differentiation / genetics
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Cells, Cultured
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Creatinine / urine
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Disease Models, Animal
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Epithelial-Mesenchymal Transition
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Fibrosis / physiopathology*
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Gene Expression Profiling
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Glutathione / metabolism
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Glutathione Disulfide / metabolism
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HIV / genetics
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HIV Infections / metabolism
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HIV Infections / pathology
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Humans
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Hydroxyproline / metabolism
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Kidney Diseases / pathology*
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Mice
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Mice, Transgenic
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Molecular Sequence Data
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NF-kappa B / metabolism
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Nuclear Proteins
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Oligonucleotide Array Sequence Analysis
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Oxidative Stress / physiology
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / metabolism*
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RNA, Small Interfering / metabolism
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Signal Transduction / genetics
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Smad3 Protein / metabolism
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Time Factors
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Transfection
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Transforming Growth Factor beta1 / metabolism
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Tumor Suppressor Protein p53 / metabolism
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Ubiquitin-Protein Ligases
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Up-Regulation / genetics
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Up-Regulation / physiology*
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Wnt Signaling Pathway / genetics
Substances
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Carrier Proteins
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NF-kappa B
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Nuclear Proteins
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RNA, Small Interfering
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Smad3 Protein
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Transforming Growth Factor beta1
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Tumor Suppressor Protein p53
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Creatinine
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Ubiquitin-Protein Ligases
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seven in absentia proteins
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Hipk2 protein, mouse
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Protein Serine-Threonine Kinases
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Glutathione
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Hydroxyproline
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Glutathione Disulfide