title: Vasohibin-1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction.
abstract: 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 mRNA, 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 siRNA 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.
authors: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors: Hiroyuki
authors: H
authors: Watatani
authors: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors: Yohei
authors: Y
authors: Maeshima
authors: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors: Norikazu
authors: N
authors: Hinamoto
authors: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors: Hiroko
authors: H
authors: Yamasaki
authors: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors: Haruyo
authors: H
authors: Ujike
authors: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors: Katsuyuki
authors: K
authors: Tanabe
authors: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan Center for Chronic Kidney Disease and Peritoneal Dialysis, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors: Hitoshi
authors: H
authors: Sugiyama
authors: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors: Fumio
authors: F
authors: Otsuka
authors: Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan.
authors: Yasufumi
authors: Y
authors: Sato
authors: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors: Hirofumi
authors: H
authors: Makino
keywords: Inflammation; TGF‐β1; macrophage; tubulointerstitial fibrosis; unilateral ureteral obstruction; vasohibin‐1