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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.
Highlights
Renal fibrosis is the final convergent pathway for progressive chronic kidney diseases (CKDs) regardless of the original etiologies of the disease [1]
Our results indicate that the renal tubular epithelial cells (RTECs) function of homeodomain-interacting protein kinase 2 (HIPK2) is a key mediator of renal fibrosis, and that increased HIPK2 expression and kinase activity are required for kidney fibrosis progression
The loss of HIPK2 in RTECs had no effects in sham-operated kidneys; it resulted in a marked attenuation of renal fibrosis development following ureteral obstruction (UUO) when compared with control Pax8HIPK2+/+ UUO mice (Figure 1, A and B)
Summary
Renal fibrosis is the final convergent pathway for progressive chronic kidney diseases (CKDs) regardless of the original etiologies of the disease [1]. Recent evidence suggests that TGF-β, Wnt, and Notch signaling pathways promote fibrosis in the setting of kidney disease [7,8,9,10] Their inhibitors have not yet been tested or proven successful in clinical trials [11]. HIPK2 expression was elevated in various human kidney diseases and associated with renal fibrosis progression [12] We showed that it promotes renal fibrosis by potentiating the signaling cascades of TGF-β, Wnt, Notch, and NF-κB pathways. The central role of HIPK2 was previously confirmed from observations that the genetic ablation of Hipk in mice [12] and BT173, a small molecule inhibitor of HIPK2 [13], markedly attenuated kidney fibrosis and improved kidney function in experimental models of kidney disease These data strongly support the role of HIPK2 as a key driver of fibrosis in kidney disease, the effect of HIPK2 function in renal tubular epithelial cells (RTECs) or other cell types in this process was unclear.
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