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Published on: November 10, 2021
Tubular HIPK2 is a key contributor to renal fibrosis
Wenzhen Xiao1, Jing E1,2, Li Bao1,2
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Abstract:
We previously used global Hipk2-null mice in various models of kidney disease to demonstrate the central role of homeodomain-interacting protein kinase 2 (HIPK2) in renal fibrosis development. However, renal tubular epithelial cell-specific (RTEC-specific) HIPK2 function in renal fibrogenesis has yet to be determined. Here, we show that modulation of tubular HIPK2 expression and activity affects renal fibrosis development in vivo. The loss of HIPK2 expression in RTECs resulted in a marked diminution of renal fibrosis in unilateral ureteral obstruction (UUO) mouse models and HIV-associated nephropathy (HIVAN) mouse models, which was associated with the reduction of Smad3 activation and downstream expression of profibrotic markers. Conversely, WT HIPK2 overexpression in RTECs accentuated the extent of renal fibrosis in the setting of UUO, HIVAN, and folic acid-induced nephropathy in mice. Notably, kinase-dead HIPK2 mutant overexpression or administration of BT173, an allosteric inhibitor of HIPK2-Smad3 interaction, markedly attenuated the renal fibrosis in these mouse models of kidney disease, indicating that HIPK2 requires both the kinase activity and its interaction with Smad3 to promote TGF-β-mediated renal fibrosis. Together, these results establish an important RTEC-specific role of HIPK2 in kidney fibrosis and further substantiate the inhibition of HIPK2 as a therapeutic approach against renal fibrosis.
Insights
Homeodomain-interacting protein kinase 2 (HIPK2) in kidney tubule cells drives kidney fibrosis. Inhibiting HIPK2 kinase activity or its interaction with Smad3 reduces fibrosis, suggesting HIPK2 as a therapeutic target for kidney disease.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Homeodomain-interacting protein kinase 2 (HIPK2) is implicated in renal fibrosis.
- The specific role of HIPK2 within renal tubular epithelial cells (RTECs) in kidney fibrogenesis remains unclear.
Purpose of the Study:
- To investigate the RTEC-specific function of HIPK2 in the development of kidney fibrosis.
- To determine if HIPK2 kinase activity and its interaction with Smad3 are essential for promoting renal fibrosis.
Main Methods:
- Utilized global Hipk2-null mice and generated RTEC-specific HIPK2 modulation models.
- Employed unilateral ureteral obstruction (UUO), HIV-associated nephropathy (HIVAN), and folic acid-induced nephropathy mouse models.
- Assessed renal fibrosis, Smad3 activation, and profibrotic marker expression.
Main Results:
- Loss of HIPK2 in RTECs significantly reduced renal fibrosis in UUO and HIVAN models, correlating with decreased Smad3 activation.
- Overexpression of wild-type HIPK2 in RTECs exacerbated fibrosis in UUO, HIVAN, and folic acid-induced nephropathy models.
- Kinase-dead HIPK2 mutant or BT173 (HIPK2-Smad3 inhibitor) administration attenuated renal fibrosis, highlighting the importance of HIPK2's kinase activity and Smad3 interaction.
Conclusions:
- HIPK2 plays a critical RTEC-specific role in promoting kidney fibrosis.
- HIPK2 mediates TGF-β-induced renal fibrosis through its kinase activity and interaction with Smad3.
- Inhibiting HIPK2 represents a promising therapeutic strategy for treating kidney fibrosis.
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