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Kidney Week

Abstract: TH-PO546

Auto-Inhibitory Domain of HIPK2 Is a Novel Inhibitor of NF-κB Signaling in Kidney Cells

Session Information

  • Pathology and Lab Medicine
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pathology and Lab Medicine

  • 1700 Pathology and Lab Medicine


  • Feng, Ye, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States

We previously identified HIPK2 as a key protein kinase that regulates pro-apoptotic (p53), pro-fibrotic (TGF-β) and pro-inflammatory (NF-κB) pathways in renal tubular cells (RTEC) and diseased kidneys. As HIPK2 has multiple functional domains, mapping the individual domains required for distinct downstream pathway activation may be an optimal approach towards targeting specific HIPK2-dependent pathway. In this study, we have elucidated a novel function and mechanism of auto-inhibitory domain (AID) of HIPK2 (HIPK2-AID) in regulation of renal inflammation and fibrosis.


Plasmids encoding different functional domains of HIPK2 were constructed. To determine the functional role of HIPK2-AID in RTEC, we used HK2 cells. In vivo, we generated a mouse model in which expression of HIPK2-AID is induced specifically in RTECs. In this model, we examined the effects of HIPK2-AID on renal inflammation and fibrosis after creation of unilateral ureteral obstruction (UUO).


We identified that HIPK2-AID fragment was released after Caspase 6-mediated cleavage of HIPK2. Interestingly, HIPK2-AID could act as a dominant negative to suppress TNFα-induced NF-κB (p65) transcriptional activation in HK2 cells. Mechanistically, HIPK2-AID’s interaction with p65 resulted in its cytoplasmic sequestration, thereby reducing its transcriptional activity: Co-localization of p65 and HIPK2-AID in cytosol was confirmed by confocal microscopic analysis. In TNFα-stimulated cells, HIPK2-AID attenuated IκB-α phosphorylation and blocked p65 nuclear translocation, resulting in NF-κB pathway inactivation. Consistently, overexpression of HIPK2-AID specifically in RTECs attenuated p65 nuclear translocation in tubular cells and reduced macrophage infiltration in the kidney of UUO mice. The levels of p65 and IκB-α phosphorylation in the UUO kidneys were also downregulated with HIPK2-AID overexpression.


Collectively, our findings suggest that HIPK2-AID functions as a potential inhibitor of NF-κB signaling and HIPK2-AID or its analogues could be developed as anti-inflammatory agents to treat kidney disease.


  • NIDDK Support