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Kidney Week

Abstract: SA-PO132

Increased HIPK2 Expression in Tubular Epithelial Cells Aggravates Kidney Fibrosis

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Xiao, Wenzhen, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • E, Jing, 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, Mount Sinai School of Medicine, New York, New York, United States
Background

Irrespective of etiology, kidney fibrosis is a final common pathogenic process for the progression of chronic kidney disease (CKD) to end-stage renal disease. Therefore, there is an urgent need to develop effective anti-fibrosis therapy for CKD. We previously demonstrated that homeodomain interacting protein kinase 2 (HIPK2) is a critical protein kinase regulating multiple pro-fibrotic and pro-inflammatory pathways in the diseased kidney. The global knockout of HIPK2 attenuates kidney fibrosis in several animal models of kidney disease. However, the direct effects of HIPK2 in renal tubular cells have not been confirmed. Therefore, we used several conditional knockout or expressing mouse models to further investigate the role of HIPK2 in renal tubular epithelial cells in kidney fibrosis.

Methods

We generated tetracycline-inducible, tubule-specific HIPK2 knockout mice (Hipk2fl/fl; pax8-rtTA; TRE-Cre). We also generated tetracycline-inducible tubule-specific HIPK2 wildtype overexpression mice (Hipk2WT; pax8-rtTA), as well as kinase-dead HIPK2 mutant mice (Hipk2MT; pax8-rtTA) as a control. Tetracycline analog doxycycline was administered for 3 weeks prior to unilateral ureter obstruction (UUO) and at the age of five-week-old Tg26 mice. Extent of fibrosis was assessed after 14 days of UUO and at the age of 10-week-old Tg26 mice by histopathological scoring and by assessment of fibrosis markers using quantitative PCR and western blot.

Results

We observed that the loss of tubular HIPK2 resulted in significant attenuation of kidney fibrosis, while tubular overexpression of wildtype HIPK2 resulted in marked augmentation of kidney fibrosis in UUO mice. Furthermore, the overexpression of kinase-dead HIPK2 mutant significantly diminished kidney fibrosis in UUO mice and Tg26 mice, suggesting that the kinase activity of HIPK2 is required for its pro-fibrosis effect.

Conclusion

Our results clearly demonstrate that increased HIPK2 expression in renal tubular cells aggravates kidney fibrosis progression. Therefore, the inhibitors of HIPK2 could be developed as a potential anti-fibrotic therapy for CKD.

Funding

  • NIDDK Support