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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Am+Soc+Nephrol
2017 ; 28
(7
): 2133-2143
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A Novel Inhibitor of Homeodomain Interacting Protein Kinase 2 Mitigates Kidney
Fibrosis through Inhibition of the TGF-?1/Smad3 Pathway
#MMPMID28220029
Liu R
; Das B
; Xiao W
; Li Z
; Li H
; Lee K
; He JC
J Am Soc Nephrol
2017[Jul]; 28
(7
): 2133-2143
PMID28220029
show ga
Homeodomain interacting protein kinase 2 (HIPK2) is a critical regulator of
multiple profibrotic pathways, including that of TGF-?1/Smad3. Genetic ablation
of HIPK2 was shown previously to significantly reduce renal fibrosis in the
experimental unilateral ureteral obstruction model and Tg26 mice, a model of
HIV-associated nephropathy. To develop specific pharmacologic inhibitors of HIPK2
for antifibrotic therapy, we designed and synthesized small molecule inhibitor
compounds on the basis of the predicted structure of HIPK2. Among these
compounds, we identified one, BT173, that strongly inhibited the ability of HIPK2
to potentiate the downstream transcriptional activity of Smad3 in kidney tubular
cells. Notably, binding of BT173 to HIPK2 did not inhibit HIPK2 kinase activity
but rather, interfered allosterically with the ability of HIPK2 to associate with
Smad3. In vitro, treatment with BT173 inhibited TGF-?1-induced Smad3
phosphorylation and Smad3 target gene expression in human renal tubular
epithelial cells. In vivo, administration of BT173 decreased Smad3
phosphorylation and mitigated renal fibrosis and deposition of extracellular
matrix in unilateral ureteral obstruction and Tg26 mouse models of renal
fibrosis. Our data indicate that BT173 is a novel HIPK2 inhibitor that attenuates
renal fibrosis through suppression of the TGF-?1/Smad3 pathway and may be
developed as an antifibrotic therapy in patients with kidney disease.
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