Serum Sortilin Is Associated with Coronary Artery Calcification and Cardiovascular and Cerebrovascular Events in Maintenance Hemodialysis Patients.

OBJECTIVE: To analyze the role of serum sortilin in coronary artery calcification (CAC) and cardiovascular and cerebrovascular events (CCE) in maintenance hemodialysis (MHD) patients. METHODS: One hundred eleven patients with MHD ≥3 months were included in this study. The general data, clinical features, hematological data, and medication history of the patients were recorded. Eighty-five cases were examined by vascular color Doppler ultrasound, cardiac color Doppler ultrasound, lateral lumbar radiography, and coronary artery calcification score. The patients were followed up for a median time of 45 months. The primary endpoint was CCE or death from a vascular event, and the role of sortilin in this process was analyzed. RESULTS: Among 85 MHD patients, 51 cases (60.00%) had different degrees of CAC. There were significant differences in diabetes, dialysis time, serum phosphorus, calcium-phosphorus product, medical history of phosphate binders, sortilin, and carotid artery plaque between 4 different degrees of calcification groups (p < 0.05). Logistic regression analysis showed that diabetes (OR = 5.475; 95% CI: 1.794-16.71, p = 0.003), calcium-phosphorus product (OR = 2.953; 95% CI: 1.198-7.279, p = 0.019), and sortilin (OR = 1.475 per 100 pg/mL; 95% CI: 1.170-1.858, p = 0.001) were independent risk factors for CAC. During the follow-up, 28 cases of 111 patients (25.23%) suffered from CCE. There were significant differences in CCE between mild, moderate, and severe CAC groups and noncalcification groups (p < 0.05). Cox regression analysis showed that diabetes mellitus (HR 3.424; 95% CI: 1.348-8.701, p = 0.010), CAC (HR 5.210; 95% CI: 1.093-24.83, p = 0.038), and serum sortilin (HR = 8.588; 95% CI: 1.919-38.43, p = 0.005) were independent risk factors for CCE. Besides, we proposed a cutoff value of 418 pg/mL for serum sortilin level, which was able to predict the occurrence of CCE with 75.0% sensitivity and 71.9% specificity. The area under the curve was 0.778 (95% CI: 0.673-0.883). CONCLUSION: Sortilin is newly found to be independently associated with CAC and CCE in MHD patients.

Single-Cell Profiling Reveals Transcriptional Signatures and Cell-Cell Crosstalk in Anti-PLA2R Positive Idiopathic Membranous Nephropathy Patients.

Idiopathic membranous nephropathy (IMN) is an organ-specific autoimmune disease of the kidney glomerulus. It may gradually progress to end-stage renal disease (ESRD) characterized by increased proteinuria, which leads to serious consequences. Although substantial advances have been made in the understanding of the molecular bases of IMN in the last 10 years, certain questions remain largely unanswered. To define the transcriptomic landscape at single-cell resolution, we analyzed kidney samples from 6 patients with anti-PLA2R positive IMN and 2 healthy control subjects using single-cell RNA sequencing. We then identified distinct cell clusters through unsupervised clustering analysis of kidney specimens. Identification of the differentially expressed genes (DEGs) and enrichment analysis as well as the interaction between cells were also performed. Based on transcriptional expression patterns, we identified all previously described cell types in the kidney. The DEGs in most kidney parenchymal cells were primarily enriched in genes involved in the regulation of inflammation and immune response including IL-17 signaling, TNF signaling, NOD-like receptor signaling, and MAPK signaling. Moreover, cell-cell crosstalk highlighted the extensive communication of mesangial cells, which infers great importance in IMN. IMN with massive proteinuria displayed elevated expression of genes participating in inflammatory signaling pathways that may be involved in the pathogenesis of the progression of IMN. Overall, we applied single-cell RNA sequencing to IMN to uncover intercellular interactions, elucidate key pathways underlying the pathogenesis, and identify novel therapeutic targets of anti-PLA2R positive IMN.

A Partial Picture of the Single-Cell Transcriptomics of Human IgA Nephropathy.

The molecular mechanisms underlying renal damage of IgA nephropathy (IgAN) remain incompletely defined. Here, single-cell RNA sequencing (scRNA-seq) was applied to kidney biopsies from IgAN and control subjects to define the transcriptomic landscape at single-cell resolution. We presented a comprehensive scRNA-seq analysis of human renal biopsies from IgAN. We showed for the first time that IgAN mesangial cells displayed increased expression of several novel genes including MALAT1, GADD45B, SOX4, and EDIL3, which were related to cell proliferation and matrix accumulation. The overexpressed genes in tubule cells of IgAN were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling, and NOD-like receptor signaling. Furthermore, we compared the results of 4 IgAN patients with the published scRNA-Seq data of healthy kidney tissues of three human donors in order to further validate the findings in our study. The results also verified that the overexpressed genes in tubule cells from IgAN patients were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling, and NOD-like receptor signaling. The receptor-ligand crosstalk analysis revealed potential interactions between mesangial cells and other cells in IgAN. IgAN patients with overt proteinuria displayed elevated genes participating in several signaling pathways compared with microproteinuria group. It needs to be mentioned that based on number of mesangial cells and other kidney cells analyzed in this study, the results of our study are preliminary and needs to be confirmed on larger number of cells from larger number of patients and controls in future studies. Therefore, these results offer new insight into pathogenesis and identify new therapeutic targets for IgAN.

Neferine inhibits LPS-ATP-induced endothelial cell pyroptosis via regulation of ROS/NLRP3/Caspase-1 signaling pathway.

BACKGROUND: Oxidative stress-induced endothelial dysfunction and pyroptosis play an important role during chronic kidney disease (CKD) progression. Neferine, which is an alkaloid ingredient from the lotus seed embryo, has many biological actions such as anti-inflammatory, anticancer and antioxidant. However, the role of neferine in endothelial cell pyroptosis and the involved mechanism remain obscure. The aim is to probe the protective effects of neferine on cell pyroptosis and the involved underlying mechanism. METHODS: After the HUVECs were primed with neferine treatment for 2 h prior to LPS and ATP exposure for 24 h, the cell proliferation was determined by BrdU; the cell LDH release was detected by LDH kits; the levels of intracellular ROS, MDA and SOD were tested by detection kits; Caspase-1 activity kit was used to determine caspase-1 activity; the contents of NLRP3, ASC, caspase-1, IL-1ß, IL-18 and GSDMD were tested by RT-PCR and western blot. RESULTS: We found that neferine could inhibit LPS-ATP-induced oxidative stress and the activation of NLRP3 inflammasome signaling, and increased the endothelial cell viability and SOD production. siRNA which mediated the knockdown of NLRP3 promoted the neferine-induced inhibition effects of cell pyroptosis. Furthermore, these neferine-induced effects were reversed by the over-expression of NLRP3. CONCLUSIONS: Our findings indicated neferine may reduce ROS by anti-oxidation and inhibit LPS-ATP-induced endothelial cell pyroptosis via blocking ROS/NLRP3/Caspase-1 signaling pathway, which provides the evidence for therapeutic effect in CKD.

Reduced cerebrovascular reactivity in posterior cerebral arteries in patients with primary open-angle glaucoma.

PURPOSE: To evaluate the hemodynamics and vasoreactivity in the posterior cerebral artery (PCA) in patients with primary open-angle glaucoma (POAG). DESIGN: Case-control study. PARTICIPANTS: Thirteen POAG patients (age range, 40-60 years) with marked visual field loss (mean deviation [MD], <-6 dB); a preserved, mostly normal, central visual field of at least 5°; and best-corrected visual acuity of at least 20/40 formed the study group. Exclusion criterion was presence or history of any systemic disorder including cardiovascular diseases. The control group consisted of 12 healthy subjects matched for age and sex with the study group. METHODS: Applying transcranial Doppler sonography, we measured hemodynamic parameters in both PCAs at baseline, under monocular reversing checkerboard stimulation, and under hyperventilation. The eye with more marked visual field loss was selected in glaucoma patients, whereas in controls, the tested eye was chosen randomly. Ipsilateral and contralateral PCA were defined according to the tested eye. MAIN OUTCOME MEASURES: Peak systolic velocity (PSV), end-diastolic velocity, mean velocity (MV), MV change percentage (MV%), resistivity index (RI), pulsatility index (PI). RESULTS: At baseline, RI (0.55 ± 0.04 vs. 0.52 ± 0.03; P = 0.04) and PI (0.88 ± 0.11 vs. 0.80 ± 0.07; P = 0.04) in the ipsilateral PCA were significantly higher in glaucoma patients than in controls. During checkerboard stimulation, MV% in both PCAs were significantly smaller in the glaucoma group than in controls (19.7 ± 7.2% and 19.0 ± 8.3% vs. 30.7 ± 7.9% and 27.5±9.0%, respectively; P = 0.001 and 0.02, respectively). During hyperventilation, glaucoma patients showed significantly lower MV% in the contralateral PCA than control subjects (-39.8 ± 9.6% versus -47.4 ± 7.0%; P = 0.03). Perimetric pattern standard deviation (PSD) in the tested eye was correlated significantly with RI and PI of the ipsilateral PCA during checkerboard stimulation (P = 0.003, r = -0.76; and P = 0.002, r = -0.76). The MV% of contralateral PCA was correlated inversely with PSD in the fellow eye (P = 0.02, r = -0.64). The difference in MV% between both PCAs was correlated positively with the difference in MD between 2 eyes (P = 0.003, r = 0.75). Under hyperventilation, PSV in the contralateral PCA was correlated negatively with the PSD in the fellow eye (P = 0.03, r = -0.60). CONCLUSIONS: Vascular insufficiency in the PCAs may be associated with POAG. Changes in the vasoreactivity of PCAs to central visual stimulation may precede marked central visual field loss.