Vasohibin-1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction.

Tubulointerstitial injuries are known to predict the deterioration of renal function in chronic kidney disease ( CKD). We recently reported the protective role of Vasohibin-1( VASH-1), a negative feedback regulator of angiogenesis, in diabetic nephropathy, but its impact on tubulointerstitial injuries remains to be elucidated. In the present study, we evaluated the role of endogenous VASH-1 in regulating the tubulointerstitial alterations induced by unilateral ureteral obstruction ( UUO), and assessed its role on fibrogenesis and the activation of Smad3 signaling in renal fibroblasts. UUO was induced in female Vasohibin-1 heterozygous knockout mice ( VASH-1+/−) or wild-type ( WT) ( VASH-1+/+) littermates. Mice were sacrificed on Day 7 after left ureter ligation, and the kidney tissue was obtained. Interstitial fibrosis, the accumulation of type I and type III collagen and monocytes/macrophages infiltration in the obstructed kidneys ( OBK) were significantly exacerbated in VASH-1+/− mice compared with WT mice (Day 7). The increases in the renal levels of TGF- β1, pSmad3, NF- κB pp65, CCL2 m RNA, and the number of interstitial fibroblast-specific protein-1 (FSP-1)+ fibroblasts in the OBK were significantly aggravated in VASH-1+/− mice. In addition, treatment with VASH-1 si RNA enhanced the TGF- β1-induced phosphorylation of Smad3, the transcriptional activation of the Smad3 pathway and the production of type I/type III collagen in fibroblasts, in vitro. Taken together, our findings demonstrate a protective role for endogenous VASH-1 on tubulointerstitial alterations via its regulation of inflammation and fibrosis and also show the direct anti-fibrotic effects of VASH-1 on renal fibroblasts through its modulation of TGF- β1 signaling. [ABSTRACT FROM AUTHOR]