Citation Information: JCI Insight. 2020. https://doi.org/10.1172/jci.insight.136004.
Abstract
Using the global Hipk2-null mice in various models of kidney disease, we previously demonstrated the central role of homeodomain interacting protein kinase 2 (HIPK2) in the development of renal fibrosis. However, whether the renal tubular epithelial cell (RTEC)-specific HIPK2 function significantly contributed to renal fibrogenesis had not been established. Herein, using RTEC-specific HIPK2 null mice and transgenic mice with RTEC-specific overexpression of the wildtype (WT) or kinase-dead (KD) mutant of HIPK2, we now show that the modulation of tubular HIPK2 expression and activity can profoundly affect renal fibrosis development in vivo. The loss of HIPK2 expression in RTECs resulted in a marked diminution of renal fibrosis in mouse models of unilateral obstruction (UUO) and HIV-associated nephropathy (HIVAN) in Tg26 mice, which was associated with the reduction of Smad3 activation and downstream expression of profibrotic markers. Conversely, the overexpression of WT HIPK2 in RTECs accentuated the extent of renal fibrosis in the setting of UUO, HIVAN, and folic acid nephropathy (FAN) in mice. Importantly, the overexpression of HIPK2 KD mutant 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--mediated renal fibrosis. Together, these results establish an important RTEC-specific role of HIPK2 in kidney fibrosis and further substantiates the inhibition of HIPK2 as a therapeutic approach toward renal fibrosis.
Authors
Wenzhen Xiao, Jing E, Li Bao, Ying Fan, Yuanmeng Jin, Andrew Wang, David Bauman, Zhengzhe Li, Ya-Li Zheng, Ruijie Liu, Kyung Lee, John Cijiang He
