title: Defect in Runx2 gene accelerates ureteral obstruction-induced kidney fibrosis via increased TGF-β signaling pathway.
abstract: Runt-related transcription factor 2 (Runx2) plays an important role in bone formation and de novo synthesis of proteins, including type 1 collagen. Runx2 has a potent effect on signaling of transforming growth factor (TGF)-β and vice versa, implicating its significant role in fibrosis. Chronic renal failure comprises fibrosis, characterized as an increase in TGF-β signaling, and expression of α-smooth muscle actin (α-SMA), and extracellular matrix proteins. Here, we evaluated the role of Runx2 in ureteral obstruction (UO)-induced kidney fibrosis using mice whose Runx2 gene expression is genetically down-regulated. UO caused tubular atrophy and dilation, expansion of interstitium, and increased expression of collagens and α-SMA with a concomitant decrease in expression of Runx2. Deficiency of Runx2 gene (Runx2(+/-) mice) showed higher expression of collagens and α-SMA in the kidney following UO compared to wild type (Runx2(+/+)) mice. UO-induced activation of TGF-β signaling was higher in the Runx2(+/-) kidney than Runx2(+/+) kidney, suggesting an inhibitory effect of Runx2 on TGF-β signaling in kidney fibrosis. Besides, overexpression of the Runx2 gene using an adenoviral vector in kidney tubule cells resulted in attenuated TGF-β-induced Smad3 phosphorylation and expressions of α-SMA and collagen I. Furthermore, Runx2 gene deficient mouse embryonic fibroblasts induced greater activation of Smad3 and expression of α-SMA in response to TGF-β. Collectively, Runx2 plays a protective role in UO-induced kidney fibrosis by inhibition of TGF-β signaling, suggesting Runx2 as a novel target for protection against fibrosis-related diseases such as chronic renal failure.
authors: Department of Anatomy and BK21, Kyungpook National University School of Medicine, Republic of Korea.
authors: Jee In
authors: JI
authors: Kim
authors: Hee-Seong
authors: HS
authors: Jang
authors: Jae-Hwan
authors: JH
authors: Jeong
authors: Mi Ra
authors: MR
authors: Noh
authors: Je-Yong
authors: JY
authors: Choi
authors: Kwon Moo
authors: KM
authors: Park
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics*; D017931:DNA Primers; D004285:Dogs; D005355:Fibrosis / Q000209:etiology* / Q000235:genetics; D007674:Kidney Diseases / Q000209:etiology* / Q000235:genetics; D008297:Male; D051379:Mice; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000150:complications / Q000235:genetics*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D017931:DNA Primers; C493716:Runx2 protein, mouse; D016212:Transforming Growth Factor beta
keywords: Fibrosis; Runx2; Smad3; TGF-β; Ureteral obstruction