2. Academic Validation
  3. SPHK1/S1P/S1PR pathway promotes the progression of peritoneal fibrosis by mesothelial-mesenchymal transition

SPHK1/S1P/S1PR pathway promotes the progression of peritoneal fibrosis by mesothelial-mesenchymal transition

  • FASEB J. 2024 Jan 31;38(2):e23417. doi: 10.1096/fj.202301323R.
Tingting Zhao 1 2,  Tao Ding 3,  Zhengyu Sun 1,  Xin Shao 4,  Shuangxi Li 1,  Hongtao Lu 5,  Ji-Hang Yuan 6,  Zhiyong Guo 1
Affiliations

Affiliations

  • 1 Department of Nephrology, First Affiliated Hospital of Naval Medical University, Shanghai Changhai Hospital, Shanghai, China.
  • 2 Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 3 Department of Endocrinology, Xizang Military General Hospital, Lhasa City, China.
  • 4 Department of Cardiovascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 5 Department of Nutrition, Naval Medical University, Shanghai, China.
  • 6 Department of Medical Genetics, Naval Medical University, Shanghai, China.
PMID: 38226856 DOI: 10.1096/fj.202301323R
Abstract

Long-term exposure to non-physiologically compatible dialysate inevitably leads to peritoneal fibrosis (PF) in patients undergoing peritoneal dialysis (PD), and there is no effective prevention or treatment for PF. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid produced after catalysis by sphingosine kinase (SphK) 1/2 and activates signals through the S1P receptor (S1PR) via autocrine or paracrine. However, the role of SPHK1/S1P/S1PR signaling has never been elucidated in PF. In our research, we investigated S1P levels in peritoneal effluents and demonstrated the role of SPHK1/S1P/S1PR pathway in peritoneal fibrosis. It was found that S1P levels in peritoneal effluents were positively correlated with D/P Cr (r = 0.724, p < .001) and negatively correlated with 4 h ultrafiltration volume (r = -0.457, p < .001). S1PR1 and S1PR3 on peritoneal cells were increased after high glucose exposure in vivo and in vitro. Fingolimod was applied to suppress S1P/S1PR pathway. Fingolimod restored mouse peritoneal function by reducing interstitial hyperplasia, maintaining ultrafiltration volume, reducing peritoneal transport solute rate, and mitigating the protein expression changes of fibronectin, vimentin, α-SMA, and E-cadherin induced by PD and S1P. Fingolimod preserved the morphology of the human peritoneal mesothelial cells, MeT-5A, and moderated the mesothelial-mesenchymal transition (MMT) process. We further delineated that SPHK1 was elevated in peritoneal cells after high glucose exposure and suppression of SPHK1 in MeT-5A cells reduced S1P release. Overexpression of SPHK1 in MeT-5A cells increased S1P levels in the supernatant and fostered the MMT process. PF-543 treatment, targeting SPHK1, alleviated deterioration of mouse peritoneal function. In conclusion, S1P levels in peritoneal effluent were correlated with the deterioration of peritoneal function. SPHK1/S1P/S1PR pathway played an important role in PF.

Keywords

Fingolimod; Sphingosine-1-phosphate; peritoneal fibrosis; sphingosine kinase.

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