title: A Novel Inhibitor of Homeodomain Interacting Protein Kinase 2 Mitigates Kidney Fibrosis through Inhibition of the TGF-β1/Smad3 Pathway.
abstract: Homeodomain interacting protein kinase 2 (HIPK2) is a critical regulator of multiple profibrotic pathways, including that of TGF-β1/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-β1-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-β1/Smad3 pathway and may be developed as an antifibrotic therapy in patients with kidney disease.
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Ruijie
authors.initials: R
authors.lastname: Liu
authors.affiliation: Division of Nephrology, Department of Medicine and.|Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Das
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Zhengzhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: Division of Nephrology, Department of Medicine and.|Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; and.
authors.forename: Huilin
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Nephrology, Department of Medicine and.
authors.forename: Kyung
authors.initials: K
authors.lastname: Lee
authors.affiliation: Division of Nephrology, Department of Medicine and cijiang.he@mssm.edu.|Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.|Renal Section, James J. Peters Veterans Affairs Medical Center, Bronx, New York.
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D005355:Fibrosis / Q000517:prevention & control; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010069:Oxadiazoles / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D051900:Smad3 Protein / Q000037:antagonists & inhibitors*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: C000622121:BT173 compound; D002352:Carrier Proteins; D010069:Oxadiazoles; D011804:Quinolines; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C115114:HIPK2 protein, human; C492003:Hipk2 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: HIPK2; Smad3; TGF-beta; renal fibrosis; tubular cells