PD Solutions and Peritoneal Health

Cho, Yeoungjee; Johnson, David W.

doi:10.2215/cjn.09590818

Cited by 6 publications

(2 citation statements)

References 10 publications

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“…Peritoneal dialysis (PD) remains the leading form of home-based dialysis for the treatment of end-stage kidney disease [1,2]. Efficiency of PD depends on a healthy and functional peritoneal membrane [3]. Unfortunately, long-term exposure of the peritoneum to bioincompatible, glucose-based dialysis solutions often results in progressive fibrotic lesions, characterized by enhanced production of Ivyspring International Publisher profibrotic factors and excessive deposition of extracellular matrix.…”

Section: Introductionmentioning

confidence: 99%

Restoration of CPT1A-mediated fatty acid oxidation in mesothelial cells protects against peritoneal fibrosis

Su,

Hu,

Zhong

et al. 2023

Theranostics

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Background: Peritoneal dialysis (PD) is limited by gradual fibrotic remodeling in the peritoneum, a process involving profibrotic response of mesothelial cells. However, the role of fatty acid oxidation (FAO) and carnitine palmitoyltransferase 1A (CPT1A) in this process remains unexplored. Methods: FAO and CPT1A expression were characterized in mesothelial cells from patients on long-term PD and from a mouse model of PD using multiple experimental methods, including single-cell sequencing, seahorse assay, real-time quantitative PCR, Western blot, and immunofluorescence staining. Overexpression of CPT1A was achieved in a human mesothelial cell line and in primary mouse mesothelial cells. Finally, genetic and pharmacological manipulations of CPT1A were performed in a mouse model of PD. Results: Herein, FAO and CPT1A expression were reduced in mesothelial cells from patients on long-term PD, which negatively correlated with expression of fibrogenic markers in these cells. This was corroborated in PD mice, as well as in mouse and human mesothelial cells incubated with transforming growth factor (TGF) β1. CPT1A overexpression in mesothelial cells, which prevented TGFβ1-induced suppression of mitochondrial respiration, restored cellular ATP levels and downregulated the expression of fibrogenic markers. Furthermore, restoration of FAO by overexpressing CPT1A in PD mice reversed profibrotic phenotype in mesothelial cells and reduced fibrotic lesions in the peritoneum. Treatment with the CPT1A activator C75 induced similar therapeutic benefit in PD mice. In contrast, inhibition of FAO with a CPT1 inhibitor caused more severe fibrosis in PD mice. Conclusions: A defective FAO is responsible for the profibrotic response of mesothelial cells and thus the peritoneal fibrogenesis. This aberrant metabolic state could be improved by modulating CPT1A in mesothelial cells, suggesting FAO enhancement in mesothelial cells is a potential treatment of peritoneal fibrosis.

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Section: Introductionmentioning

confidence: 99%

Restoration of CPT1A-mediated fatty acid oxidation in mesothelial cells protects against peritoneal fibrosis

Su,

Hu,

Zhong

et al. 2023

Theranostics

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“…Several factors contribute to peritoneal inflammation during long-term PD. These factors include (1) the inflammatory status of chronic kidney disease as a result of a reduction in the renal clearance of cytokines, fluid overload, immunological dysfunction and infectious comorbidity 4 , (2) long-term exposure of the peritoneal membrane to unphysiological dialytic solutions with high glucose and low pH 5 , (3) PD-related peritonitis 6 , (4) uremia-induced inflammation in the peritoneum 7 , and (5) protein energy wasting 8 . These factors are usually related to one other and eventually lead to peritoneal fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Expression of XBP1s in peritoneal mesothelial cells is critical for inflammation-induced peritoneal fibrosis

Liu

Song

Zheng

et al. 2019

Sci Rep

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Intraperitoneal inflammation is the most important determinant of peritoneal fibrosis in patients with long-term peritoneal dialysis (PD). Spliced x-box binding protein-1 (XBP1s), a major proximal effector of unfolded protein response (UPR) signaling, plays an indispensable role in inflammation. Our study demonstrated that the inflammatory factor interleukin-1β (IL-1β) dose-and time-dependently induced XBP1s upregulation and interleukin-6 (IL-6) secretion, as well as the expression of the fibrotic marker fibronectin. However, these effects were prevented by the IRE1 endonuclease inhibitor STF083010 since it time-dependently reduced IL-1β-induced Xbp1 mRNA splicing, XBP1s protein expression, inflammatory factor IL-6 secretion and the expression of the fibrotic marker fibronectin in human peritoneal mesothelial cells (HPMCs). The overexpression and knockdown of XBP1s in HPMCs had a similar effect on fibronectin expression. In a rat model of peritoneal inflammation, STF083010 significantly attenuated chlorhexidine digluconate-induced XBP1s and α-smooth muscle actin expression, as well as fibrotic tissue proliferation, in the peritoneum. Our results suggest that XBP1s is a strong pathogenic factor that mediates inflammation-induced peritoneal fibrosis in peritoneal dialysis.Peritoneal dialysis (PD) is one of the major effective forms of renal replacement for the treatment of end stage renal diseases (ESRD) 1 , especially within the first five years of dialysis. The population of patients undergoing PD has recently begun to increase sharply throughout the world, particularly in developing countries such as China, due to the implementation of improved healthcare policies 2 . However, the advantages of PD gradually weaken after the first five years of dialysis because of chronic peritoneal dysfunction, which is characterized by inflammation, peritoneal fibrosis and neo-angiogenesis at the lesion site 3 .Several factors contribute to peritoneal inflammation during long-term PD. These factors include (1) the inflammatory status of chronic kidney disease as a result of a reduction in the renal clearance of cytokines, fluid overload, immunological dysfunction and infectious comorbidity 4 , (2) long-term exposure of the peritoneal membrane to unphysiological dialytic solutions with high glucose and low pH 5 , (3) PD-related peritonitis 6 , (4) uremia-induced inflammation in the peritoneum 7 , and (5) protein energy wasting 8 . These factors are usually related to one other and eventually lead to peritoneal fibrosis. Therefore, intraperitoneal inflammation-induced peritoneal fibrosis is the greatest challenge for long-term PD therapy thus far.Inositol-requiring enzyme-1α (IRE1α)/X-box-binding protein 1 (XBP1) signaling is the most important pathway for the unfolded protein response (UPR)/endoplasmic reticulum (ER) stress. It has been revealed that, upon ER stress, unconventional splicing of Xbp1 mRNA occurs to generate spliced Xbp1 (Xbp1s) 9 . Xbp1s encodes an active transcription factor, XBP1s, which drives the expression of...

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Peritoneal Dialysis Solutions

Harvey

2021

Pediatric Dialysis

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PD Solutions and Peritoneal Health

Cited by 6 publications

References 10 publications

Restoration of CPT1A-mediated fatty acid oxidation in mesothelial cells protects against peritoneal fibrosis

Restoration of CPT1A-mediated fatty acid oxidation in mesothelial cells protects against peritoneal fibrosis

Expression of XBP1s in peritoneal mesothelial cells is critical for inflammation-induced peritoneal fibrosis

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