Defect in Runx2 gene accelerates ureteral obstruction-induced kidney fibrosis via increased TGF-β signaling pathway

• Ureteral obstruction down-regulated expression of Runx2 in the kidney.
• Reduction of Runx2 gene enhanced ureteral obstruction-induced renal fibrosis.
• Reduction of Runx2 gene enhanced ureteral obstruction-induced renal inflammation.
• Reduction of Runx2 gene enhanced ureteral obstruction-induced TGF-β signaling.
• Overexpression of Runx2 inhibited TGF-β-induced epithelial mesenchymal transition.

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.