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Deficiency of endothelial nitric oxide signaling pathway exacerbates peritoneal fibrosis in mice

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Abstract

Background

Long-term peritoneal dialysis (PD) causes peritoneal dysfunction and structural alterations, eventually leading to peritoneal fibrosis. The endothelial nitric oxide synthase (eNOS)–NO signaling pathway contributes to the progression of organ fibrosis. However, it remains unknown whether NO signaling is involved in the process of peritoneal fibrosis. We evaluated the role of the eNOS–NO signaling pathway in the development of peritoneal fibrosis and whether stimulation of soluble guanylate cyclase (sGC), a downstream effector of NO, could attenuate peritoneal fibrosis.

Methods

We used wild-type (WT) and eNOS-deficient mice (eNOSKO). The mice underwent mechanical peritoneal stripping-induced peritoneal fibrosis at day 0. At 3, 7, 14, and 28 days after peritoneal stripping, the mice were killed. In some eNOSKO mice, the sGC stimulator Bay 41-2272 was administered by intraperitoneal injection.

Results

In WT mice, granulomatous tissue formation was observed in the submesothelial area at days 3 and 7. After day 7, the peritoneal membrane thickness gradually decreased and peritoneal tissue was repaired with leaving only slight fibrosis at day 28. However, eNOSKO mice demonstrated more progression of peritoneal fibrosis than WT mice at 28 days after peritoneal stripping. Expression of vimentin in the thickened peritoneum was prolonged after day 7 in eNOSKO mice. Treatment with Bay 41-2272 significantly attenuated peritoneal vimentin expression and fibrosis in the eNOSKO mice.

Conclusions

Disruption of the eNOS–NO signaling pathway exacerbates peritoneal fibrosis by delaying wound healing. sGC stimulation may be a useful therapy for prevention of peritoneal fibrosis.

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Acknowledgments

This study was supported by a Research Project Grant from Kawasaki Medical School. We wish to thank Ms. Etsuko Yorimasa, Ms. Miki Ishihara, and Ms. Miyuki Yokohata for animal care, and Ms. Satomi Hanada, Ms. Keiko Satoh, and Ms. Yoshiko Shirakiya for help with in vitro experiments.

Disclosure

All the authors have declared no competing interest.

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Authors and Affiliations

  1. Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, 701-0192, Japan

    Hiroyuki Kadoya, Minoru Satoh, Hajime Nagasu, Tamaki Sasaki & Naoki Kashihara

Authors
  1. Hiroyuki Kadoya
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  2. Minoru Satoh
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  3. Hajime Nagasu
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  4. Tamaki Sasaki
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  5. Naoki Kashihara
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Correspondence to Minoru Satoh.

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Kadoya, H., Satoh, M., Nagasu, H. et al. Deficiency of endothelial nitric oxide signaling pathway exacerbates peritoneal fibrosis in mice. Clin Exp Nephrol 19, 567–575 (2015). https://doi.org/10.1007/s10157-014-1029-3

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  • DOI: https://doi.org/10.1007/s10157-014-1029-3

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