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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...

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Autores principales: Watatani, Hiroyuki, Maeshima, Yohei, Hinamoto, Norikazu, Yamasaki, Hiroko, Ujike, Haruyo, Tanabe, Katsuyuki, Sugiyama, Hitoshi, Otsuka, Fumio, Sato, Yasufumi, Makino, Hirofumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wiley Periodicals, Inc. 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208642/
https://www.ncbi.nlm.nih.gov/pubmed/24973329
http://dx.doi.org/10.14814/phy2.12054
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author Watatani, Hiroyuki
Maeshima, Yohei
Hinamoto, Norikazu
Yamasaki, Hiroko
Ujike, Haruyo
Tanabe, Katsuyuki
Sugiyama, Hitoshi
Otsuka, Fumio
Sato, Yasufumi
Makino, Hirofumi
author_facet Watatani, Hiroyuki
Maeshima, Yohei
Hinamoto, Norikazu
Yamasaki, Hiroko
Ujike, Haruyo
Tanabe, Katsuyuki
Sugiyama, Hitoshi
Otsuka, Fumio
Sato, Yasufumi
Makino, Hirofumi
author_sort Watatani, Hiroyuki
collection PubMed
description 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.
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spelling pubmed-42086422014-11-25 Vasohibin‐1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction Watatani, Hiroyuki Maeshima, Yohei Hinamoto, Norikazu Yamasaki, Hiroko Ujike, Haruyo Tanabe, Katsuyuki Sugiyama, Hitoshi Otsuka, Fumio Sato, Yasufumi Makino, Hirofumi Physiol Rep Original Research 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. Wiley Periodicals, Inc. 2014-06-27 /pmc/articles/PMC4208642/ /pubmed/24973329 http://dx.doi.org/10.14814/phy2.12054 Text en © 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society. http://creativecommons.org/licenses/by/3.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Watatani, Hiroyuki
Maeshima, Yohei
Hinamoto, Norikazu
Yamasaki, Hiroko
Ujike, Haruyo
Tanabe, Katsuyuki
Sugiyama, Hitoshi
Otsuka, Fumio
Sato, Yasufumi
Makino, Hirofumi
Vasohibin‐1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction
title Vasohibin‐1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction
title_full Vasohibin‐1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction
title_fullStr Vasohibin‐1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction
title_full_unstemmed Vasohibin‐1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction
title_short Vasohibin‐1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction
title_sort vasohibin‐1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208642/
https://www.ncbi.nlm.nih.gov/pubmed/24973329
http://dx.doi.org/10.14814/phy2.12054
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