Systems Approach Identifies HIPK2 as a Critical Regulator of Kidney Tubulointerstitial Fibrosis audioicon

Tubulointerstitial fibrosis is a common process that leads to the progression of kidney disease. We describe an integrated computational/experimental approach to identify upstream protein kinases that regulate gene expression changes in kidneys of HIV-1 transgenic mice (Tg26), a model for HIV-associated nephropathy (HIVAN), which exhibits significant tubulointerstitial injury. We performed both gene expression microarrays and protein/DNA interaction arrays on renal cortical samples from Tg26 and wild type (WT) controls. We deduced transcription factors (TFs) from microarray studies using TRANSFEC and Chip-ChiP databases.

We combined the list of TFs identified from DNA/protein arrays with the TFs predicted from microarray datasets. We then identified proteins interacting with these TFs using Gene2network. Finally, we ranked potential protein kinases that are likely to regulate the phosphorylation of these proteins. From this ranking, we identified the homeo-domain interacting protein kinase 2 (HIPK2), a previously unrecognized protein kinase for kidney disease, is critically involved in the progression of renal tubulointerstitial injury and fibrosis. HIPK2 is highly expressed in the renal tubulointerstitium of Tg26 as well as in patients with HIVAN and other kidney diseases. HIV infection increases protein levels of HIPK2 through stimulation of ROS production and inhibition of Siah1-mediated HIPK2 proteasomal degradation. HIPK2 induces apoptosis and expression of epithelial-mesenchymal transition markers in renal tubular epithelial cells through activation of p53, TGF-?/Smad3, and Wnt/Notch pathways. Knockout of HIPK2 attenuated activity of these pathways and tubulointerstitial fibrosis in Tg26 as well as in other two models of kidney fibrosis (Folic acid induced nephropathy and unilateral ureteral obstruction). We conclude that HIPK2 is a critical regulator of kidney fibrosis and a potential target for anti-fibrosis therapy.

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This was presented at the ISN Forefronts Symposium event “Systems Biology and the Kidney” that took place from 7-10 June 2012 in AnnArbor , Michigan, US.

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Last modified on Saturday, 22 March 2014 20:10

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