BMSC-derived Exosomes Ameliorate Peritoneal Dialysis-associated Peritoneal Fibrosis via the Mir-27a-3p/TP53 Pathway.

OBJECTIVE: Peritoneal fibrosis (PF) is the main cause of declining efficiency and ultrafiltration failure of the peritoneum, which restricts the long-term application of peritoneal dialysis (PD). This study aimed to investigate the therapeutic effects and mechanisms of bone marrow mesenchymal stem cells-derived exosomes (BMSC-Exos) on PF in response to PD. METHODS: Small RNA sequencing analysis of BMSC-Exos was performed by second-generation sequencing. C57BL/6J mice were infused with 4.25% glucose-based peritoneal dialysis fluid (PDF) for 6 consecutive weeks to establish a PF model. A total of 36 mice were randomly divided into 6 groups: control group, 1.5% PDF group, 2.5% PDF group, 4.25% PDF group, BMSC-Exos treatment group, and BMSC-Exos+TP53 treatment group. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed to measure the expression level of miR-27a-3p in BMSC-Exos and peritoneum of mice treated with different concentrations of PDF. HE and Masson staining were performed to evaluate the extent of PF. The therapeutic potential of BMSC-Exos for PF was examined through pathological examination, RT-qPCR, Western blotting, and peritoneal function analyses. Epithelial-mesenchymal transition (EMT) of HMrSV5 was induced with 4.25% PDF. Cells were divided into control group, 4.25% PDF group, BMSC-Exos treatment group, and BMSC-Exos+TP53 treatment group. Cell Counting Kit-8 assay was used to measure cell viability, and transwell migration assay was used to verify the capacity of BMSC-Exos to inhibit EMT in HMrSV5 cells. RESULTS: Small RNA sequencing analysis showed that miR-27a-3p was highly expressed in BMSC-derived exosomes compared to BMSCs. The RT-qPCR results showed that the expression of miR-27a-3p was upregulated in BMSC-Exos, but decreased in PD mice. We found that PF was glucose concentration-dependently enhanced in the peritoneum of the PD mice. Compared with the control mice, the PD mice showed high solute transport and decreased ultrafiltration volume as well as an obvious fibroproliferative response, with markedly increased peritoneal thickness and higher expression of α-SMA, collagen-I, fibronectin, and ECM1. The mice with PD showed decreased miR-27a-3p. Peritoneal structural and functional damage was significantly attenuated after BMSC-Exos treatment, while PF and mesothelial damage were significantly ameliorated. Additionally, markers of fibrosis (α-SMA, collagen-I, fibronectin, ECM1) and profibrotic cytokines (TGF-ß1, PDGF) were downregulated at the mRNA and protein levels after BMSC-Exos treatment. In HMrSV5 cells, BMSC-Exos reversed the decrease in cell viability and the increase in cell migratory capacity caused by high-glucose PDF. Western blotting and RT-qPCR analysis revealed that BMSC-Exos treatment resulted in increased expression of E-cadherin (epithelial marker) and decreased expression of α-SMA, Snail, and vimentin (mesenchymal markers) compared to those of the 4.25% PDF-treated cells. Importantly, a dual-luciferase reporter assay showed that TP53 was a target gene of miR-27a-3p. TP53 overexpression significantly reversed the decreases in PF and EMT progression induced by BMSC-Exos. CONCLUSION: The present results demonstrate that BMSC-Exos showed an obvious protective effect on PD-related PF and suggest that BMSC-derived exosomal miR-27a-3p may exert its inhibitory effect on PF and EMT progression by targeting TP53.

Association of Sleep Duration with Physical Performance in Hemodialysis Patients: A Multicenter Cross-Sectional Study.

BACKGROUND: Hemodialysis (HD) patients have decreased physical function. Getting enough sleep is important for maintaining physical function. However, the relationship between sleep duration and physical performance in HD patients is unclear. METHODS: We conducted a multicenter cross-sectional study at seven HD centers in Shanghai and Suzhou, China. 880 HD patients were enrolled between July 2020 and April 2021. Clinical Characteristics, laboratory indicator, sleep assessment data were collected. Physical performance included balance function, muscle strength, and mobility, which were measured by timed up and go test (TUGT), handgrip, and 4-m walk test, respectively. We divided sleep duration into four groups <7 h, 7-8 h, >8-9 h, ≥9 h. RESULTS: A total of 840 patients had completed data (men 525, women 315, mean age 61.24 years). TUGT in group <7 h and ≥9 h was higher than mid-range sleep duration. Handgrip strength in group ≥9 h was lower than group <7 h and 7-8 h. Gait speed in group <7 h and ≥9 h was lower than group 7-8 h. Adjusting for the covariates, short and long sleep duration were associated with slower gait speed. CONCLUSION: HD patients with abnormal sleep duration had poorer physical performance. Short and long sleep duration were significantly associated with gait speed.

Mediating effect of gait speed on the relationship between ankle-brachial index and mild cognitive impairment in hemodialysis patients.

BACKGROUND: Patients undergoing hemodialysis are highly predisposed to arterial disease, poor physical performance, and cognitive impairment. However, the connection between them is not yet known. We aimed to investigate the mediating effect of physical performance on the relationship between arterial stiffness and mild cognitive impairment (MCI). METHODS: We conducted a multicenter cross-sectional study. The final analyzed hemodialysis patients comprised 616 subjects (men 391, women 225) from seven dialysis units in Shanghai, China. MCI was assessed by Mini-Mental State Examination (MMSE) and the Instrumental Activities of Daily Living (IADL) scale. Arterial function was measured by ankle-brachial index (ABI) and branchial-ankle pulse-wave velocity (baPWV). Physical function was assessed by the Short Physical Performance Battery (SPPB). Logistic regression and mediation model were used to analysis. RESULTS: The mean age of the final analysis sample (n = 616) was 59.0 ± 12.0 years. Hemodialysis patients with MCI were more likely to have lower ABI (p < 0.001) and higher baPWV (p < 0.01). After adjusting for covariates, lower ABI (abnormal ≤0.9 and borderline 0.91-0.99) were positively associated with MCI (OR = 4.43, 95% CI = 1.89-10.39; OR = 4.83, 95% CI = 1.61-14.46). SPPB total score and its components standing balance, gait speed score were negatively associated with MCI. In the mediational model, gait speed played a mediating role (indirect effect ab = -0.21; 95% CI = -0.58 to -0.03) in the association of ABI (≤0.9) and MMSE, while standing balance and chair stands did not. CONCLUSIONS: Lower gait speed mediates a positive association between ABI and MCI in hemodialysis patients. Suitable interventions for physical performance, especially gait speed, may reduce the risk of MCI in hemodialysis patients.