The association of left ventricular fraction shortening with cardiovascular events in peritoneal dialysis patients.

BACKGROUND: Peritoneal dialysis (PD) patients have a high incidence of cardiovascular events (CVEs). Left ventricular fraction shortening (LVFS), one of the echocardiographic parameters, is an independent risk factor for mortality in previous studies. The aim of this study was to evaluate associations between LVFS and CVEs in PD patients. METHODS: This was a single-center observational cohort study. Seven hundred and eighty-four PD patients were enrolled from 1 January 2012 to 1 June 2021 and followed until 1 June 2022. The primary outcome was the incidence of CVEs. PD patients were categorized into three groups according to the tertiles of LVFS levels (tertile 1-tertile 3). Kaplan-Meier method, Cox proportional hazard models and competing risk regression models were used for survival analysis. The areas under the curve (AUC) of receiver-operating characteristic analysis was used to determine the predictive values of LVFS for CVEs. A preplanned subgroup analysis was assessed according to age, gender, and the presence of hypertension and dyslipidemia, etc. RESULTS: During a median follow-up period of 42.3 months (interquartile range 24.0-79.0 months), 259 CVEs occurred. Compared to the other two groups respectively, patients in tertile 3 group had the lowest incidence of CVEs (24.5% vs 31.6% vs 43.0%, respectively, p < 0.05). After multiple adjustments, the tertile 3 group was associated with the 45.1% decrease in the CVEs hazard compared to that of the tertile1 group (SHR = 0.549, 95%CI: 0.395-0.762, p < 0.001). Subgroup analysis demonstrated that tertile 1 group as the reference, the association between LVFS and CVEs in tertile 3 group was robust among female patients (HR = 0.506, 95%CI: 0.309-0.829, p = 0.007), aged < 45 years (HR = 0.496, 95%CI: 0.331-0.744, p = 0.001), history of hypertension (HR = 0.586, 95%CI: 0.349-0.872, p = 0.008) and combined with dyslipidemia (HR = 0.464, 95%CI: 0.269-0.799, p = 0.006). CONCLUSIONS: This study suggests that LVFS is independently associated with the increased risk of CVEs in PD patients, especially those with aged < 45 years, female, with hypertension and dyslipidemia.

[1, 25-(OH)2-VitD3 attenuates renal tubulointerstitial fibrosis in diabetic kidney disease by inhibiting Snail1-SMAD3/SMAD4 complex formation].

Objective To investigate the effect of 1, 25-(OH)2-VitD3 (VitD3) on renal tubuleinterstitial fibrosis in diabetic kidney disease. Methods NRK-52E renal tubular epithelial cells were divided into control group (5.5 mmol/L glucose medium treatment), high glucose group (25 mmol/L glucose medium treatment) and high glucose with added VitD3 group (25 mmol/L glucose medium combined with 10-8 mmol/L VitD3). The mRNA and protein expression of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in NRK-52E cells were detected by real-time quantitative PCR and Western blot analysis respectively. The expression and localization of Snail1, SMAD3 and SMAD4 were detected by immunofluorescence cytochemical staining. The binding of Snail1 with SMAD3/SMAD4 complex to the promoter of Coxsackie-adenovirus receptor (CAR) was detected by chromatin immunoprecipitation. The interaction among Snail1, SMAD3/SMAD4 and E-cadherin were detected by luciferase assay. Small interfering RNA (siRNA) was used to inhibit the expression of Snail1 and SMAD4, and the expression of mRNA of E-cadherin was detected by real-time quantitative PCR. SD rats were randomly divided into control group, DKD group and VitD3-treated group. DKD model was established by injection of streptozotocin (STZ) in DKD group and VitD3-treated group. After DKD modeling, VitD3-treated group was given VitD3 (60 ng/kg) intragastric administration. Control group and DKD group were given normal saline intragastric administration. In the DKD group and VitD3-treated group, insulin (1-2 U/kg) was injected subcutaneously to control blood glucose for 8 weeks. The mRNA and protein levels of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in renal tissues were detected by real-time quantitative PCR and Western blot analysis respectively. Immunohistochemistry was used to detect the expression and localization of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in renal tissue. Results Compared with the control group, the mRNA and protein expressions of Snail1, SMAD3, SMAD4 and α-SMA in NRK-52E cells cultured with high glucose and in DKD renal tissues were up-regulated, while E-cadherin expression was down-regulated. After the intervention of VitD3, the expression levels of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in the DKD model improved to be close to those in the control group. Chromatin immunoprecipitation showed that Snail1 and SMAD3/SMAD4 bound to CAR promoter IV, while VitD3 prevented Snail1 and SMAD3/SMAD4 from binding to CAR promoter IV. Luciferase assay confirmed the interaction among Snail1, SMAD3/SMAD4 and E-cadherin. After the mRNA of Snail1 and SMAD4 was inhibited by siRNA, the expression of E-cadherin induced by high glucose was up-regulated. Conclusion VitD3 could inhibit the formation of Snail1-SMAD3/SMAD4 complex and alleviate the renal tubulointerstitial fibrosis in DKD.

Dendrobium officinale Kimura & Migo polysaccharide inhibits hyperglycaemia-induced kidney fibrosis via the miRNA-34a-5p/SIRT1 signalling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Fibrosis is a fundamental change occurring in impaired renal function and plays an important role in the progression of diabetic kidney disease (DKD). Dendrobium officinale Kimura & Migo polysaccharide (DOP), a primary active component of Dendrobium officinale Kimura & Migo, is reported to act on reducing blood glucose, suppressing inflammation. However, the anti-fibrosis effect of DOP in the treatment of DKD is still unclear. AIM OF THE STUDY: To explore the therapeutic effect of DOP on renal fibrosis in DKD. MATERIALS AND METHODS: We used db/db mice as a DKD model and administered DOP by oral gavage. The expression of miRNA-34a-5p, SIRT1, and fibrosis molecules (TGF-ß, CTGF, and a-SMA) were detected in renal tissue. Human renal tubular epithelium cells (HK-2) were cultured with 5.5 mM glucose (LG) or 25 mM glucose (HG), and intervened with 100-400 µg/ml DOP. The changes of the above indicators were observed in vitro. RESULTS: MiRNA-34a-5p was mainly localised in the nucleus and increased expression in the DKD mice. Inhibition or excitation of miRNA-34a-5p is involved in renal fibrosis by regulating SIRT1. DOP could depress the miRNA-34a-5p/SIRT1 signalling pathway to relieve renal fibrosis. Moreover, DOP has outstanding results in the treatment of DKD through hypoglycaemic action and weight reduction. CONCLUSIONS: DOP plays a protective role in arresting or slowing the progression of fibrosis, which may provide a novel clinical treatment strategy for DKD.