DNMT1-Mediated the Downregulation of FOXF1 Promotes High Glucose-induced Podocyte Damage by Regulating the miR-342-3p/E2F1 Axis.

Podocyte damage plays a crucial role in the occurrence and development of diabetic nephropathy (DN). Accumulating evidence suggests that dysregulation of transcription factors plays a crucial role in podocyte damage in DN. However, the biological functions and underlying mechanisms of most transcription factors in hyperglycemia-induced podocytes damage remain largely unknown. Through integrated analysis of data mining, bioinformatics, and RT-qPCR validation, we identified a critical transcription factor forkhead box F1 (FOXF1) implicated in DN progression. Moreover, we discovered that FOXF1 was extensively down-regulated in renal tissue and serum from DN patients as well as in high glucose (HG)-induced podocyte damage. Meanwhile, our findings showed that FOXF1 might be a viable diagnostic marker for DN patients. Functional experiments demonstrated that overexpression of FOXF1 strikingly enhanced proliferation, outstandingly suppressed apoptosis, and dramatically reduced inflammation and fibrosis in HG-induced podocytes damage. Mechanistically, we found that the downregulation of FOXF1 in HG-induced podocyte damage was caused by DNMT1 directly binding to FOXF1 promoter and mediating DNA hypermethylation to block FOXF1 transcriptional activity. Furthermore, we found that FOXF1 inhibited the transcriptional expression of miR-342-3p by binding to the promoter of miR-342, resulting in reduced sponge adsorption of miR-342-3p to E2F1, promoting the expression of E2F1, and thereby inhibiting HG-induced podocytes damage. In conclusion, our findings showed that blocking the FOXF1/miR-342-3p/E2F1 axis greatly alleviated HG-induced podocyte damage, which provided a fresh perspective on the pathogenesis and therapeutic strategies for DN patients.

Association of T Cell Subsets and Platelet/Lymphocyte Ratio with Long-Term Complications in Kidney Transplant Recipients.

BACKGROUND Infection and chronic rejection remain major issues for kidney transplant recipients (KTRs). The present study aimed to explore the association of CD4+/CD8+ T cell ratio (CD4+/CD8+) and platelet/lymphocyte ratio (PLR) with long-term infection and chronic renal insufficiency in KTRs. MATERIAL AND METHODS KTRs admitted to a single hospital from June 2014 to December 2021 were divided into infected (164) and non-infected (107) groups based on clinical data. The levels of CD4+/CD8+, PLR, neutrophil/lymphocyte ratio (NLR), and C-reactive Protein (CRP) in KTRs with long-term infection, and their correlation with chronic kidney insufficiency, were analyzed. Survival analysis was used to evaluate the risk factors for long-term infection and chronic kidney insufficiency. RESULTS Spearman correlation analysis showed that chronic kidney insufficiency was positively correlated with PLR, and negatively correlated with CRP and CD4+/CD8+ (P<0.05). PLR was positively correlated with CRP, procalcitonin, erythrocyte sedimentation rate, and NLR, but negatively with CD4+/CD8+. CD4+/CD8+ was correlated with CRP, NLR, and PLR (P<0.05). Survival analysis and survival curves showed that PLR and CD4+/CD8+ were risk factors for long-term infection and chronic kidney insufficiency in KTRs (P<0.05). CONCLUSIONS CD4+/CD8+ and PLR were associated with long-term complications, and were risk factors for long-term infection and chronic kidney insufficiency in KTRs.

Hsa_circ_0001162 Inhibition Alleviates High Glucose-Induced Human Podocytes Injury by the miR-149-5p/MMP9 Signaling Pathway.

Emerging evidences suggested that circular RNAs (circRNAs) are involved in diabetic nephropathy (DN). Accumulating evidence had suggested that the degree of podocyte is a major prognostic determinant of DN progression. However, the function and in-depth mechanisms of hsa_circ_0001162 in podocyte injury of DN remain unclear. Hsa_circ_0001162 expression was detected by real-time quantitative PCR (RT-qPCR) in peripheral blood of DN patients and high glucose-induced podocytes injury model. The cell counting kit 8, 5-ethynyl-2'-deoxyuridine, flow cytometry with Annexin V-FITC/PI staining, caspase-3 activity assay Kit, enzyme linked immunosorbent assay (ELISA), RT-qPCR and western blotting were used to evaluate the effect of hsa_circ_0001162 / miR-149-5p / MMP9 axis on high glucose-induced podocyte injury. Mechanistically, dual luciferase reporter was used to confirm the relationship of miR-149-5p and hsa_circ_0001162 or MMP9. Furthermore, RNA-pull down and immunoprecipitation assay were implemented to verify the potential regulatory effects of EIF4A3 on biogenesis of hsa_circ_0001162. Our results showed that hsa_circ_0001162 was highly expressed in peripheral blood of DN patients and high glucose-induced podocytes injury model, and the knockdown of hsa_circ_0001162 increased the proliferation, inhibited the apoptosis, and suppressed inflammatory response in high glucose-induced podocytes injury. Mechanism studies demonstrated that EIF4A3 bound with flanking sequences of hsa_circ_0001162 to promote hsa_circ_0001162 expression, upregulated hsa_circ_0001162 increased the MMP9 expression via sponging miR-149-5p, thus aggravating the high glucose-induced podocytes injury. Overall, our data demonstrated that knockdown of hsa_circ_0001162 inhibited high glucose-induced podocytes injury by regulating miR-149-5p/MMP9 axis, and intervention of hsa_circ_0001162/miR-149-5p/MMP9 axis may be a potentially promising therapeutic strategy for podocyte injury in DN patients.

Protective Effect of Salidroside on Mitochondrial Disturbances via Reducing Mitophagy and Preserving Mitochondrial Morphology in OGD-induced Neuronal Injury.

Salidroside is the active ingredient extracted from Rhodiola rosea, and has been reported to show protective effects in cerebral ischemia, but the exact mechanisms of neuronal protective effects are still unrevealed. In this study, the protective effects of salidroside (1 µmol/L) in ameliorating neuronal injuries induced by oxygen-glucose deprivation (OGD), which is a classical model of cerebral ischemia, were clarified. The results showed that after 8 h of OGD, the mouse hippocampal neuronal cell line HT22 cells showed increased cell death, accompanied with mitochondrial fragmentation and augmented mitophagy. However, the cell viability of HT22 cells showed significant restoration after salidroside treatment. Mitochondrial morphology and mitochondrial function were effectively preserved by salidroside treatment. The protective effects of salidroside were further related to the prevention of mitochondrial over-fission. The results showed that mTOR could be recruited to the mitochondria after salidroside treatment, which might be responsible for inhibiting excessive mitophagy caused by OGD. Thus, salidroside was shown to play a protective role in reducing neuronal death under OGD by safeguarding mitochondrial function, which may provide evidence for further translational studies of salidroside in ischemic diseases.

Diagnosis and treatment of a patient with Kimura's disease associated with nephrotic syndrome and lymphadenopathy of the epitrochlear nodes.

BACKGROUND: Kimura's disease (KD) is a slowly progressing rare, benign inflammatory disorder of the soft tissues. It typically presents as subcutaneous tumor-like nodules, located most frequently in the head and neck region. KD is often accompanied by increased peripheral eosinophilia and elevated levels of serum immunoglobulin (Ig) E. There is renal involvement in approximately 12-16% of KD cases. We report the case of a 23-year-old Chinese man who was found to have KD associated with nephrotic syndrome. CASE PRESENTATION: A 23-year-old Chinese man presented with edema in both legs and a mass in ulnar side of his right upper arm on August 8(th) 2013. Before admission to our hospital, an ultrasound examination revealed swollen lymph nodes in the medial aspect of his right upper arm, proximal to the elbow. The patient was admitted on August 19(th) 2013 as a result of edema, severe proteinuria, and low serum albumin levels. He had a white blood cell count of 7.7 × 10(9) cells/L, 48.5% eosinophils, 4+ albuminuria, 24-hour urinary protein excretion 9.3 g, serum protein 50.3 g/L; serum albumin 16 g/L and IgE 1,510 IU/ml. A biopsy of the epitrochlear nodes revealed eosinophilic hyperplastic lymphogranulomatous tissue. A renal biopsy indicated focal segmental glomerulosclerosis (FSGS) (cellular variant) with no infiltration of eosinophil in renal interstitium. The results of immune-staining on the renal biopsy were negative for IgG, IgA, IgM, C3 and C1q. The electron microscopic analysis showed podocyte effacement. His final diagnosis was Kimura's disease associated with nephrotic syndrome. He received methylprednisolone therapy as well as symptomatic treatment, and was discharged with key indicators in normal range on September 17(th) 2013. During the year following, he had methylprednisolone at a maintenance dose of 8 mg/day, and no relapses occurred up to now. CONCLUSION: Methylprednisolone therapy is effective in KD associated with nephrotic syndrome, and long-term administration of methylprednisolone at maintenance dose may be a way to prevent relapses of KD.

Malnutrition-inflammation score predicts long-term mortality in Chinese PD patients.

BACKGROUND: Malnutrition-Inflammation Score (MIS) has proved to predict the prospective mortality in maintenance hemodialysis (MHD) patients. However, its value of long-term mortality predictability in peritoneal dialysis (PD) patients has not been adequately studied. METHODS: A total of 155 chronic stable PD patients from November 2005 to December 2006 were enrolled. At baseline, the MIS, Subjective Global Assessment (SGA), as well as clinical, laboratory, and anthropometric parameters were recorded. All patients were followed until October 2009 to evaluate mortality as a primary outcome. RESULTS: The MIS correlated very well with SGA and other nutrition and inflammation markers. Patients with a higher MIS had a worse survival rate compared to those with lower MIS. After adjusting for potential confounding factors, one unit increase of MIS was associated with a 1.27-fold greater death risk (hazard ratio: 1.27, 95% confidence interval: 1.19 - 1.36; p < 0.001). MIS had a superior mortality predictability compared with SGA. Moreover, univariate and multivariate analyses denoted MIS, age, dialysis vintage, and comorbidities as independent predictors of total mortality. CONCLUSION: MIS is a promising marker for malnutrition inflammation assessment and an independent predictor of long-term mortality in Chinese PD patients.

Elevated neutrophil to lymphocyte ratio predicts overall and cardiovascular mortality in maintenance peritoneal dialysis patients.

BACKGROUND: Neutrophil to lymphocyte ratio (NLR) is widely used as a marker of inflammation and an indicator of cardiovascular outcomes in patients with coronary artery disease. However, its prognostic value in peritoneal dialysis (PD) patients is still unknown. METHODS: We studied 138 newly started PD patients and 60 healthy controls at the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. Baseline NLR as well as demographic, clinical, and biochemical parameters were recorded. All patients were followed up until March 2011 to evaluate mortality as the primary outcome. Overall and cardiovascular disease-free survival rates were compared according to NLR level. Multivariate analysis was performed to assess the prognostic value of NLR. RESULTS: Baseline NLR levels (mean 3.5 ± 1.6) were significantly increased in PD patients compared to healthy controls (mean 1.5 ± 0.5; P < 0.001). Patients with higher NLR had a higher mortality rate compared with patients with lower NLR (51.5% vs 22.9%; P = 0.006). The 1-year and 3-year overall survival rates were 86.6% and 65.9% for patients with higher NLR compared with 97% and 85.1% for patients with lower NLR (P = 0.006). Patients with higher NLR also showed a higher cardiovascular mortality rate, compared with patients with lower NLR (38% vs 7.6%; P = 0.003). The 1-year and 3-year cardiovascular event-free survival rates were 90.7% and 81.9% for patients with higher NLR, compared with 98.6% and 95.1% for patients with lower NLR. Multivariate analysis showed high NLR value was an independent risk factor for all-cause and cardiovascular mortality. CONCLUSION: Neutrophil to lymphocyte ratio is a strong predictor for overall and cardiovascular mortality in PD patients.

Association between depression and malnutrition-inflammation complex syndrome in patients with continuous ambulatory peritoneal dialysis.

OBJECTIVE: Depression, the most common psychological disorder among patients with end-stage renal disease (ESRD), is associated with poor survival. The prevalence of depression and its relation with the malnutrition-inflammation complex syndrome (MICS) have not yet been clearly defined in Chinese continuous ambulatory peritoneal dialysis (CAPD) patients. PATIENTS AND METHODS: A total of 142 patients on CAPD were enrolled in the First Affiliated Hospital of Sun Yat-Sen University. The Hamilton Depression Scale (HAMD) and the malnutrition-inflammation score (MIS) were used for depression and MICS evaluation, respectively. Clinical, socioeconomic, and malnutrition-inflammation factors were compared among patients with and without depression. Binary regression analysis was performed to investigate the independent association between depression and MICS. RESULTS: The mean HAMD and MIS scores were 7.12 ± 5.28 and 4.45 ± 3.56, respectively. According to HAMD, 37 patients (26.1%) had depression and 70 patients (49.3%) had potential depression. Older age, longer dialysis vintage, worse residual renal function, lower employment and reimbursement status, and higher comorbidity index were positively correlated with depression. Compared to non-depressed patients, the depressed ones also showed lower levels of serum albumin and higher levels of C-reactive protein (CRP). Correlation results showed that the HAMD scores were significantly and positively correlated with MIS (r = 0.46, P < 0.01). Moreover, the incidence of peritonitis was significantly higher in depressed compared to non-depressed patients. Binary regression analysis showed that MIS was the only independent risk factor for depression. CONCLUSION: Depression is commonly encountered in Chinese CAPD patients. A close relationship exists between depression and MICS.

Conservative management of pediatric nephrolithiasis caused by melamine-contaminated milk powder.

OBJECTIVE: In this article we report our experience with the diagnostic screening and management of children with melamine-induced nephrolithiasis. METHODS: A total of 1091 children younger than 4 years who had been exposed to melamine-contaminated formula from September 17 to October 12, 2008, were screened for nephrolithiasis at the department of pediatrics at Shenzhen Nanshan Hospital in China. During the clinical examination, each patient's demographic characteristics were recorded together with the details of his or her milk-consumption profile during the contamination scare and any clinical signs of poisoning. Urinary stones were detected by B-ultrasonography, and renal status was examined by a routine urine test panel and a renal function test. When urinary stones were detected, patients were ordered to cease consumption of the suspected formula, and a conservative treatment course was adopted, including infusion of fluids, urinary alkalinization, increased water consumption, and diuresis. RESULTS: Of the 1091 children screened, 12 (1.1%) were diagnosed with kidney stones. They had been exposed to the contaminated milk from 1 to 24 months. Eleven (91.7%) of these 12 patients had consumed milk with a high level of melamine content (955-2563 ppm); 1 patient (8.3%) had consumed milk with a low-level melamine content (6.2-17.0 ppm). Six patients exhibited dysuria; the remaining 6 patients were asymptomatic. All 12 patients had normal renal function, although 4 had proteinuria, and 1 had hematuria. The kidney stones were resolved within 3 to 5 days of commencing treatment in all 12 cases. CONCLUSIONS: Nephrolithiasis was associated with high melamine-exposure levels. A combination of B-ultrasonography and urinalysis is suitable for screening for pediatric nephrolithiasis caused by melamine poisoning. The condition can be resolved with a conservative treatment approach in patients without serious clinical symptoms who have normal kidney function.