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

Abstract

Kidney fibrosis is a common process that leads to the progression of kidney diseases. We used an integrated computational/experimental systems biology approach to identify upstream protein kinases that regulate gene expression changes in kidneys of HIV-1 transgenic mice (Tg26), which have both tubulo-interstitial fibrosis and glomerulosclerosis. We identified the homeo-domain interacting protein kinase 2 (HIPK2) as a key regulator of kidney fibrosis. HIPK2 was upregulated in kidneys of Tg26 and patients with various kidney diseases. HIV infection increased the protein level of HIPK2 by promoting oxidative stress, which inhibited SIAH1-mediated proteasomal degradation of HIPK2. HIPK2 induced apoptosis and expression of epithelial-mesenchymal trans-differentiation markers in kidney epithelial cells by activating p53, TGF-β/Smad3, and Wnt/Notch pathways. Knockout of HIPK2 improved renal function and attenuated proteinuria and kidney fibrosis in Tg26 as well as in other animal models of kidney fibrosis. We conclude that HIPK2 is a potential target for anti-fibrosis therapy.

Controllability analysis of the directed human protein interaction network identifies disease genes and drug targets

“…Although network topology-based properties such as hubs and modules are commonly used to identify disease genes (41)(42)(43)(44), the controllability perspective provides a complementary network analysis framework for network medicine. In particular, type-II nodes that are not distinguishable from existing network properties and without publications bias were still identified by our controllability framework as nodes of special interest.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Systemic approaches identified novel players in renal fibrosis (157), such as the homeodomain interacting protein kinase 2 (HIPK2) in HIV transgenic mice (158). In patients with chronic kidney disease or glomerulosclerosis, genome-wide association studies (GWAS) identified several susceptibility loci (159)(160)(161), including in genes for myosin heavy chain 9 (MYH9) and uromodulin (Tamm-Horsfall protein, UMOD).…”

Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase

“…These microarray data were deposited into National Center for Biotechnology Information (NCBI)'s Gene Expression Omnibus GEO record number GSE35226. 13 Supplemental Tables 1 and 2 list the differentially expressed genes with their expression levels.…”

“…13 The method predicted that the combination of an ACEI with a histone deacetylase inhibitor (HDACI) could reverse the maximal number of genes altered in Tg26 kidneys. To examine the validity of this prediction, we experimentally confirmed that ACEI and HDACI together provide additive renal protection in Tg26 mice.…”