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

Hiroyuki Watatani, Yohei Maeshima, Norikazu Hinamoto, Hiroko Yamasaki, Haruyo Ujike, Katsuyuki Tanabe, Hitoshi Sugiyama, Fumio Otsuka, Yasufumi Sato, Hirofumi Makino

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11 Citations (Scopus)

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-jB 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.

Original languageEnglish
Article numbere12054
JournalPhysiological Reports
Volume2
Issue number6
DOIs
Publication statusPublished - 2014

Keywords

  • Inflammation
  • Macrophage
  • TGF-β1
  • Tubulointerstitial fibrosis
  • Unilateral ureteral obstruction
  • Vasohibin-1

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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  • Cite this

    Watatani, H., Maeshima, Y., Hinamoto, N., Yamasaki, H., Ujike, H., Tanabe, K., Sugiyama, H., Otsuka, F., Sato, Y., & Makino, H. (2014). Vasohibin-1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction. Physiological Reports, 2(6), [e12054]. https://doi.org/10.14814/phy2.12054