HIV-associated nephropathy (HIVAN) includes kidney inflammation and fibrosis. Transgenic mice (Tg26 mice) develop both tubulointerstitial fibrosis and glomerulosclerosis.
TRANSFAC, ChEA, and a protein-DNA interaction array were used to identify 18 transcription factors (TFs) differentially activated in kidneys of Tg26 mice. Using Genes2Networks, a network of proteins interacted with 18 transcription factors was generated. HIPK2 is one of the most highly ranked kinases in the network.
The authors went on to show:
1. HIPK2 was expressed in kidney, in humans and mice, and regulated by HIV;
2. SIAH1 is an upstream regulator of HIPK2;
3. HIPK2 mediates apoptosis and EMT;
4. Downstream signals include profibrotic TGF-β–Smad3, Wnt, p53 and NF-κB pathways;
5. Importantly, knockout of HIPK2 prevents kidney injury, and attenuates kidney fibrosis in Tg26 mice;
6. HIPK2 knockout prevents tubulointerstitial fibrosis in a second kidney fibrosis model (the UUO model).
While this is very exciting with the hope that blocking HIPK2 with inhibitors may be an attractive approach for renal fibrotic diseases, further studies are needed to show:
a. HIPK2 and related signaling in human disease cells in much more details; what kind of cells; possible interacting cells;
b. More importantly, cell type specific knockout to dissect the role of HIPK2 in either epithelial cells or fibroblasts.
References
Jin, Y. et al. A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nat. Med. doi:10.1038/nm.2685
http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2685.html
Jin Y, et al. A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nat Med. 2012 Mar 11. doi: 10.1038/nm.2685. [Epub ahead of print] PubMed PMID: 22406746.
TRANSFAC, ChEA, and a protein-DNA interaction array were used to identify 18 transcription factors (TFs) differentially activated in kidneys of Tg26 mice. Using Genes2Networks, a network of proteins interacted with 18 transcription factors was generated. HIPK2 is one of the most highly ranked kinases in the network.
The authors went on to show:
1. HIPK2 was expressed in kidney, in humans and mice, and regulated by HIV;
2. SIAH1 is an upstream regulator of HIPK2;
3. HIPK2 mediates apoptosis and EMT;
4. Downstream signals include profibrotic TGF-β–Smad3, Wnt, p53 and NF-κB pathways;
5. Importantly, knockout of HIPK2 prevents kidney injury, and attenuates kidney fibrosis in Tg26 mice;
6. HIPK2 knockout prevents tubulointerstitial fibrosis in a second kidney fibrosis model (the UUO model).
While this is very exciting with the hope that blocking HIPK2 with inhibitors may be an attractive approach for renal fibrotic diseases, further studies are needed to show:
a. HIPK2 and related signaling in human disease cells in much more details; what kind of cells; possible interacting cells;
b. More importantly, cell type specific knockout to dissect the role of HIPK2 in either epithelial cells or fibroblasts.
References
Jin, Y. et al. A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nat. Med. doi:10.1038/nm.2685
http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2685.html
Jin Y, et al. A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nat Med. 2012 Mar 11. doi: 10.1038/nm.2685. [Epub ahead of print] PubMed PMID: 22406746.
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