Down-regulation of the long non-coding RNA XIST ameliorates podocyte apoptosis in membranous nephropathy via the miR-217-TLR4 pathway.

NEW FINDINGS: What is the central question of this study? What is the role of the long non-coding RNA X-inactive specific transcript (XIST), which is up-regulated in injured podocytes and membranous nephropathy, in the pathogenesis of membranous nephropathy? What is the main finding and its importance? XIST was up-regulated in kidney tissue with membranous nephropathy and in injured podocytes. Down-regulation of XIST inhibited podocyte apoptosis. XIST negatively regulated miR-217, and miR-217 modulated Toll-like receptor 4. Inhibition of XIST suppressed podocyte apoptosis induced by angiotensin II via miR-217. ABSTRACT: Membranous nephropathy is often characterized by glomerular podocyte injury. Up-regulation of the long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) has been verified in membranous nephropathy and in injured podocytes. Here the role of XIST in podocyte injury and membranous nephropathy was explored. Quantitative real-time PCR and western blot were performed to detect the expression of XIST and miR-217, and Toll-like receptor 4 (TLR4) protein, respectively. Podocyte apoptosis was evaluated with flow cytometry. Interaction between XIST and miR-217 was analysed by RNA immunoprecipitation and RNA pull-down assay. A dual luciferase reporter assay was used to examine the interplay between miR-217 and TLR4. Up-regulation of the lncRNA XIST and angiotensin II (Ang II) and kidney and podocyte injury were indicated in kidney tissue of patients with membranous nephropathy. Increase of XIST and apoptosis were induced by Ang II in podocytes. Down-regulation of XIST reversed podocyte apoptosis induced by Ang II. MiR-217 was negatively regulated by XIST. MiR-217 controlled TLR4 by targeting its 3'-untranslated region. XIST modulated TLR4 through miR-217 and inhibition of XIST reduced podocyte apoptosis induced by Ang II via regulating miR-217. Down-regulation of XIST ameliorates podocyte apoptosis via the miR-217-TLR4 pathway, which may improve membranous nephropathy.

Serum C3/C4 ratio is a novel predictor of renal prognosis in patients with IgA nephropathy: a retrospective study.

IgA nephropathy (IgAN) is an autoimmune disease associated with complement activation. It is unclear whether the ratio of serum C3 and C4 concentrations (C3/C4 ratio) can predict renal outcomes in IgAN patients. A total of 1503 patients diagnosed with IgAN via renal biopsy were recorded in this study. Poor renal outcomes were defined as > 50% decrease in the baseline estimated glomerular filtration rate (eGFR) or development of end-stage renal disease (ESRD) during follow-up. In total, 712 patients meeting the exclusion/inclusion criteria were selected, and the mean follow-up period was 40.6 (12.34) months. Patients with decreased C3/C4 ratios displayed significantly more severe clinical characteristics and renal pathological features and a higher proportion of poor renal outcomes and ESRD. The optimal multivariate Cox regression models identified the C3/C4 ratio (hazard ratio (HR) 0.63, 95% CI 0.5-0.9), serum uric acid (HR 1.58, 95% CI 1.2-2.2), serum creatinine (HR 1.3, 95% CI 1.1-1.6), systolic blood pressure (HR 1.57, 95% CI 1.2-2.0) and T score (relative to T0, T1: HR 1.96, 95% CI 1.1-3.7, T2: HR 3.03, 95% CI 1.6-5.9) as strong predictors of poor renal outcomes. Subgroup analysis showed that patients with low C3/C4 ratios benefited from glucocorticoids or other immunosuppressive agents (hazard ratio 0.30 and 0.18, 95% CI 0.13-0.72 and 0.07-0.46, respectively). Serum C3/C4 ratios may be an independent novel predictor of renal outcomes in IgAN patients. Decreased C3/C4 ratios suggest poor renal outcomes and the potential to benefit from aggressive immunosuppressive therapies.

Relationship between Serum Soluble Klotho Protein and Coronary Artery Calcification and Prognosis in Patients on Maintenance Hemodialysis.

BACKGROUND: We aimed to investigate the relationship between serum soluble Klotho protein (sKlotho) level and coronary artery calcification (CAC) as well as prognosis in patients with maintenance hemodialysis (MHD). METHODS: Overall, 128 adult patients with end-stage renal failure treated with MHD were collected in the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Zhejiang Province, China in 2013. Serum sKlotho was detected by ELISA and coronary artery calcification was measured by multi-slice spiral computed tomography (MSCT). With 36 months' follow-up, death notes such as cause of death and death time were recorded. RESULTS: Patients were divided into low sKlotho group and high sKlotho group. Age, blood phosphorus level, hypertension incidence and incidence of diabetes mellitus of the patients in low sKlotho group was significantly higher than that of high sKlotho group (P<0.05). The coronary artery calcification score (CACs) of patients in high sKlotho group was significantly lower than that of low sKlotho group (P<0.001). Logistic regression showed that the decrease of sKlotho level (P<0.001) was an independent risk factor for CAC progression. The mortality of the patients in low sKlotho group was higher than that of high sKlotho group. Kaplan-Meier survival curve had shown that survival time of the patients in low sKlotho group was significantly lower than that of high sKlotho group (P<0.05). CONCLUSION: SKlotho can increase the degree of CAC. Although MHD patients with low sKlotho level had shorter survival time, sKlotho is not an independent risk factor in prediction of prognosis of MHD patients.

Correlation of serum levels of fibroblast growth factor 23 and Klotho protein levels with bone mineral density in maintenance hemodialysis patients.

OBJECTIVE: The correlation of serum fibroblast growth factor 23 (FGF-23) and Klotho protein levels with bone mineral density (BMD) in maintenance hemodialysis (MHD) patients was analyzed. METHODS: Between January 2015 and November 2015, 125 MHD patients in our hospital were enrolled. Dual-energy X-ray absorptiometry was used to examine the BMD in the femoral neck and lumbar spine of MHD patients. The patients were divided into three groups: a normal bone mass group, an osteopenia group, and an osteoporosis group. An ELISA was performed to measure serum FGF-23, Klotho protein, and 1,25(OH)2VitD3 levels. Other parameters, including calcium (Ca), phosphorus (P), and parathyroid hormone, were also measured. RESULTS: Of the 125 MHD patients, 82.40% of patients had femoral neck osteopenia, and 56.00% of patients had lumbar spinal osteopenia. The serum FGF-23 level was highest in the osteoporosis group. However, there was no significant difference in serum FGF-23 levels among the three groups, depending on femoral neck and lumbar spinal BMD (P > 0.05). Spearman's correlation analysis also pointed to a lack of correlation between serum FGF-23 levels and BMD. Among the three groups, there were significant differences in serum Klotho protein levels and femoral neck BMD (P < 0.05). Serum Klotho protein levels in the osteoporosis group were clearly lower than those in the normal bone mass group and osteopenia group (P < 0.05). Similarly, serum Klotho protein levels were significantly lower in those with lumbar spinal osteopenia as compared with those in the normal group. There was a positive correlation between serum Klotho protein levels and BMD and T values for the femoral neck and lumbar spine. The results of a multiple linear regression analysis revealed that the serum Klotho protein level was one of the main factors affecting BMD in MHD patients. CONCLUSIONS: The serum level of FGF-23 was not correlated with a change in BMD of MHD patients, whereas the serum Klotho protein level was associated with the degree of BMD. A high Klotho protein level may decrease the severity of chronic kidney disease and mineral bone disorder (CKD-MBD) in MHD patients with low BMD.

Elevated serum fibrinogen level is an independent risk factor for IgA nephropathy.

BACKGROUND: IgA nephropathy is a primary cause of renal failure, and inflammation and renal fibrosis are the main mechanisms leading to kidney damage. The serum fibrinogen level is closely related to inflammatory states, but its relationship to the prognosis of IgA nephropathy (IgAN) is unclear. MATERIALS AND METHODS: 1053 patients diagnosed with IgAN after renal biopsy were enrolled from two Nephrology Departments. Demographic and clinical data and histopathological features were collected. The patients were divided into four groups (Q1-Q4) according to the serum fibrinogen levels at the time of renal biopsy, and the relationships of serum fibrinogen levels with other risk factors and the prognosis of IgAN were investigated. RESULTS: 672 patients with proven primary IgAN were included in this study, which included a median follow-up of 36 months. Patients with higher serum fibrinogen levels had elevated serum creatinine levels, 24-hour urinary protein, and blood pressure compared with patients with the lowest levels of serum fibrinogen as well as severe renal damage at the time of renal biopsy. Univariate and multivariate Cox regression analyses confirmed that the serum fibrinogen level at the time of renal biopsy was significantly related to the prognosis of patients with IgAN. CONCLUSIONS: In patients with IgAN, an elevated serum fibrinogen level at the time of renal biopsy is associated with poor renal outcomes, which suggests the need for more aggressive early interventions. Greater benefits of aggressive treatments were observed in patients with higher serum fibrinogen levels.

Brazilin Ameliorates Diabetic Nephropathy and Inflammation in db/db Mice.

Hyperglycemia and inflammation play important roles in the pathogenesis of diabetic nephropathy (DN). Brazilin might be an effective pharmacological agent against hyperglycemia and inflammation. In our present study, we explored whether brazilin mitigated pathological progression, inflammation, and extracellular matrix (ECM) accumulation in a mouse model of diabetic nephropathy. Brazilin reduced aggravated biochemical indices of DN (proteinuria and the serum glucose level) and renal hypertrophy. Brazilin also improved renal morphology and inhibited macrophage infiltration, as manifested by different pathological staining methods. Brazilin reduced the levels of pro-inflammatory cytokines and CD68, a macrophage marker, in the kidney cortex, as revealed by both RT-PCR and western blotting experiments. Furthermore, brazilin significantly downregulated the serum levels of pro-inflammatory cytokines and chemokines. Interestingly, brazilin significantly upregulated the levels of the anti-inflammatory factor IL-10, and prevented ECM accumulation. Brazilin reduced nuclear translocation of the NF-κB p65 subunit both in vitro and in vivo. Thus, brazilin might be a useful treatment for DN, through mitigating hypoglycemia, inflammation, and ECM accumulation.