Zengchun Ye

Reversed Dipper Blood-Pressure Pattern Is Closely Related to Severe Renal and Cardiovascular Damage in Patients with Chronic Kidney Disease

Background A non-dipper blood pressure (BP) pattern is very common in chronic kidney disease (CKD) patients and affects the progression and development of cardiovascular disease. However, data on the reversed dipper BP pattern on target-organ damage in Chinese CKD patients are lacking. Methods A total of 540 CKD patients were enrolled. Ambulatory blood pressure monitoring (ABPM), clinical BP, ultrasonographic assessment and other clinical data were collected. Univariate and multivariate analyses were used to ascertain the relationship between ABPM results and clinical parameters. Results A total of 21.9% CKD patients had a reversed dipper BP pattern, 42% of patients had a non-dipper BP pattern and 36.1% of patients had a dipper BP pattern. Patients with reversed dipper BP pattern had the worst renal function and most severe cardiovascular damages among these CKD patients (p<0.05). The estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI) correlated significantly with the rate of decline of nocturnal BP. A reversed dipper BP pattern was an independent factor affecting kidney damage and left ventricular hypertrophy. Age, lower hemoglobin level, higher 24-h systolic BP from ABPM, and higher serum phosphate levels were independent associated with a reversed dipper BP pattern after multivariate logistic regression analyses. Conclusion The reversed dipper BP pattern is closely related to severe renal damage and cardiovascular injuries in CKD patients, and special attention should be given to these CKD patients.

Simvastatin Alleviates Hyperpermeability of Glomerular Endothelial Cells in Early-Stage Diabetic Nephropathy by Inhibition of RhoA/ROCK1

Background Endothelial dysfunction is an early sign of diabetic cardiovascular disease and may contribute to progressive diabetic nephropathy (DN). There is increasing evidence that dysfunction of the endothelial tight junction is a crucial step in the development of endothelial hyperpermeability, but it is unknown whether this occurs in glomerular endothelial cells (GEnCs) during the progression of DN. We examined tight junction dysfunction of GEnCs during early-stage DN and the potential underlying mechanisms. We also examined the effect of simvastatin (3-Hydroxy-3-methylglutaryl CoA reductase inhibitor) on dysfunction of the tight junctions of cultured GEnCs and in db/db mice with early-stage DN. Methods We assessed the expression of occludin and ZO-1, two major components of the tight junction complex, in cultured rat GEnCs treated with high glucose and in 12 week-old db/db mice with early-stage DN. We also investigated activation of RhoA/ROCK1 signaling, GEnC permeability, and renal function of the mice. Results High glucose suppresses occludin expression and disrupts occludin/ZO-1 translocation in GEnCs. These changes were associated with increased permeability to albumin and activation of RhoA/ROCK1 signaling. Occludin and ZO-1 dysregulation also occurred in the glomeruli of mice with early-stage DN, and these abnormalities were accompanied by albuminuria and activation of RhoA/ROCK1 in isolated glomeruli. Simvastatin prevented high glucose or hyperglycemia-induced dysregulation of occludin and ZO-1 by inhibition of RhoA/ROCK1 signaling in cultured GEnCs and in db/db mice with early-stage DN. Conclusion Our results indicate that activation of RhoA/ROCK1 by high glucose disrupts the expression and translocation of occludin/ZO-1 and that simvastatin alleviates occludin/ZO-1 dysregulation and albuminuria by suppressing RhoA/ROCK1 signaling during early-stage DN. These results suggest a potential therapeutic strategy for preventing the onset of albuminuria in early-stage DN.

Serum immunoglobulin A/C3 ratio predicts progression of immunoglobulin A nephropathy

The serum immunoglobulin A (IgA)/C3 ratio has been shown to be a good predictor of histological lesions and prognosis for patients with IgA nephropathy (IgAN) in Japanese. But its validity in the Chinese population is unclear. We sought to explore the long‐term outcomes of IgAN, its clinical and histopathological predictors in Chinese patients. In particular, the role of serum IgA/C3 ratio in the course of IgAN was addressed.

Mesangial medium from IgA nephropathy patients induces podocyte epithelial-to-mesenchymal transition through activation of the phosphatidyl inositol-3-kinase/Akt signaling pathway.

Background: Podocyte injury plays an important role in glomerulosclerosis in IgA nephropathy (IgAN). Eepithelial-to-mesenchymal transition (EMT) caused by different factors is the main reason for podocyte damage. This study hypothesized that conditioned mesangial medium may induced EMT process of podocytes and thereby lead to glomerular injury or sclerosis. Materials and Methods: Podocytes were incubated in medium from mesangial cells incubated with aggregated IgA1(aIgA1) isolated from IgAN patients. Wortmannin were used to inhibit phosphatidylinositol-3-kinase (PI3-K) in podocytes. Results: Western blot analysis, real-time PCR and confocal fluorescent microscopy demonstrated that reduced expression of P-Cadherin, Zonula occludens-1 (ZO-1) and podocin, increased expression of fibroblast –specific protein (FSP-1), α-smooth muscle action(α-SMA) and desmin in podocytes exposed to medium from mesangial cells incubated with aIgA1 isolated from IgAN patients compared with podocytes cultured in RPMI 1640 medium containing 0.5% fetal bovine serum ( FBS) (p<0.05). Mesangial medium resulted in a greater albumin influx across the podocyte monolayer (p<0.05). Phosphorylation of Akt increased with this medium, as indicated by an increase in the p-Akt/Akt ratio. Treatment with wortmannin partly restored the changes in epithelial and mesenchymal markers and albumin influx. IgAN patients with massive proteinuria showed remarkable α-SMA and FSP-1 expression in podocytes. Conclusion: Our findings indicated that mesangial medium from cells incubated with aIgA1 isolated from IgAN patients induced EMT in podocytes and the PI3-K/ Akt-signaling pathway was involved in the process.

Activation of the Nrf2-ARE Pathway Attenuates Hyperglycemia-Mediated Injuries in Mouse Podocytes

Background: Damage to podocytes caused by excessive reactive oxygen species (ROS) contributes to onset and progression of diabetic kidney disease (DKD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a redox-sensing transcription factor that can induce the expression of antioxidant enzymes. We explored whether activation of Nrf2 pathway attenuated hyperglycemia-induced injuries in mouse podocytes. Methods: Tert-Butylhydroquinone (tBHQ) and small interfering RNAs (siRNAs) were used to regulate Nrf2 expression. Apoptosis and intracellular superoxide anion production were measured by flow cytometry. The activity of the Nrf2 antioxidant pathway was measured by an antioxidant response element (ARE)-driven luciferase reporter gene assay, and Nrf2 expression was assessed by real-time PCR and western blot analyses. Results: Podocytes incubated with high-glucose (HG) medium had higher intracellular superoxide anion and hydrogen peroxide production, higher apoptosis rate, higher bovine serum albumin (BSA) permeability and lower synaptopodin expression compared with podocytes exposed normal glucose (NG) (p<0.05). tBHQ increased the activity of the Nrf2 antioxidant pathway and enhanced nuclear Nrf2 expression, reduced intracellular superoxide anion and hydrogen peroxide production, apoptosis rate and BSA permeability, and restored synaptopodin expression in podocytes exposed to HG (p<O.05). Podocytes with Nrf2 siRNAs showed higher intracellular superoxide anion and hydrogen peroxide production, apoptosis and BSA permeability as well as lower synaptopodin expression compared with podocytes exposed to HG (p<0.05). Conclusions: Our findings suggest that protection against activation of the Nrf2-ARE pathway in podocytes exposed to hyperglycemia. Thus, regulation of the Nrf2-ARE pathway could be a therapeutic option to combat oxidative stress and inhibit the development of DKD.

How increased VEGF induces glomerular hyperpermeability: a potential signaling pathway of Rac1 activation

Despite growing evidence for a pathogenic role of vascular endothelial growth factor (VEGF) in microvascular complications of diabetes, the underlying mechanism responsible for its detrimental effect remains unknown. In the current study, we hypothesized that some of the detrimental effects of VEGF on microvascular endothelial cells in the diabetic milieu stem from its aberrant signaling, which leads to perturbed tight junction assembly and increased endothelial permeability. Using an integrated in vitro approach, we investigated whether the effect of VEGF on endothelial cell permeability involves Rac1 GTPase activation and tight junction disassembly. Rac1 activity was detected by Western blotting in cell membrane protein as well as pull-down assay. The permeability of glomerular endothelial cells monolayer was detected as transendothelial electronic resistance. Then tyrosine phosphorylated occludin protein was detected by Western blotting after immunoprecipitation. N17Rac1 cells are obtained by transfection of glomerular endothelial cells with a dominant negative mutant of Rac1. The data obtained in this study indicate that activation of Rac1 GTPase contributes to VEGF-induced endothelial cell hyperpermeability. We also observed that Rac1 activation leads to increased endothelial permeability through tyrosine phosphorylation of occludin. Indeed, N17Rac1 cells dramatically attenuated the effect of VEGF on phospho-occludin and endothelial cell permeability. These results, when taken together, provide a framework for understanding the role of VEGF-induced Rac1/phospho-occludin pathway in the integrity of endothelial barrier function in the glomerulus.

Association between sleep quality and cardiovascular damage in pre-dialysis patients with chronic kidney disease

BackgroundPoor sleep quality, a novel risk factor of cardiovascular diseases (CVD), is highly prevalent in patients with chronic kidney disease (CKD). The association between poor sleep quality and cardiovascular damage in patients with CKD is unclear. This study is aimed to assess the prevalence and related risk factors of sleep disturbance and determine the relationship between sleep quality and cardiovascular damage in Chinese patients with pre-dialysis CKD.MethodsA total of 427 pre-dialysis CKD patients (mean age = 39 ± 15 years, 260 male/167 female) were recruited in this study. The demographics and clinical correlates were collected. The sleep quality was measured by the Pittsburgh Sleep Quality Index (PSQI), whereas the cardiovascular damage indicators (the Early/late diastolic peak flow velocity (E/A) ratio and left ventricular mass index (LVMI)) were determined by an echocardiographic examination.ResultsOf the CKD patients, 77.8% were poor sleepers as defined by a PSQI score > 5. Median estimated glomerular filtration rate (eGFR) was 69.4(15.8-110.9) ml/min/1.73 m2. Logistic regression analysis revealed that left ventricular hypertrophy (LVH) was independently associated with the PSQI score (OR = 1.092, 95% CI = 1.011-1.179, p = 0.025), after adjustment for age, sex and clinical systolic blood pressure, diastolic blood pressure, Phosphate, Intact parathyroid hormone (iPTH), Hemoglobin and eGFR. The linear regression analysis showed that the E/A ratios were independently associated with the PSQI score (β = -0.115, P = 0.028) after adjustment for a series of potential confounding factors.ConclusionsPoor sleep quality, which is commonly found in pre-dialysis CKD patients, is an independent factor associated with cardiovascular damage in CKD patients. Our finding implies that the association between poor sleep and CVD might be mediated by cardiac remodeling.

Mesangial medium with IgA1 from IgA nephropathy inhibits nephrin expression in mouse podocytes

Background  IgA nephropathy (IgAN) is characterized by mesangial deposition of polymeric IgA1, and podocyte injury plays an important role in glomerulosclerosis of the disease. Our previous study indicated that medium of mesangial cells co‐incubated with aggregated IgA1 (aIgA1), isolated from IgAN patients, down‐regulated nephrin expression. Yet the mechanism remains unclear.

Initiation time of renal replacement therapy on patients with acute kidney injury: A systematic review and meta-analysis of 8179 participants

The early initiation of renal replacement therapy has been recommended for patients with acute renal failure by some studies, but its effects on mortality and renal recovery are unknown. We conducted an updated meta‐analysis to provide quantitative evaluations of the association between the early initiation of renal replacement therapy and mortality for patients with acute kidney injury. After applying inclusion/exclusion criteria, 51 studies, including 10 randomized controlled trials, with a total of 8179 patients were analyzed. Analysis of the included trials showed that patients receiving early renal replacement therapy had a 25% reduction in all‐cause mortality compared to those receiving late renal replacement therapy (risk ratio [RR] 0.75, 95% CI [0.69, 0.82]). We also noted a 30% increase in renal recovery (RR 1.30, 95% CI [1.07, 1.56]), a reduction in hospitalization of 5.84 days (mean difference [MD], 95% CI [–10.27, –1.41]) and a reduction in the duration of mechanical ventilation of 2.33 days (MD, 95% CI [–3.40, –1.26]) in patients assigned to early renal replacement therapy. The early initiation of renal replacement therapy was associated with a decreased risk of all‐cause mortality compared with the late initiation of RRT in patients with acute kidney injury. These findings should be interpreted with caution given the heterogeneity between studies. Further studies are needed to identify the causes of mortality and to assess whether mortality differs by dialysis dose.

Effect of aggregated immunoglobulin A1 from immunoglobulin A nephropathy patients on nephrin expression in podocytes.

Aim:  Abnormal immunoglobulin (Ig)A1 is considered to play a pivotal role in IgA nephropathy. We used mouse podocytes as the experimental model to investigate the effect of aggregated IgA1 (aIgA1) isolated from IgA nephropathy (IgAN) patients on nephrin expression in podocytes through direct and indirect pathways.