Chronic exercise improves renal AT1 and ETB receptor functions via modulating GRK4 expression in obese Zucker rats.

BACKGROUND: Physical activity has profound benefits on health, especially in patients with cardiovascular and metabolic disease. Exercise training can reduce oxidative stress, improve renal function, and thus lower blood pressure. However, the effect of exercise training on angiotensin II type 1 receptors (AT1R) and endothelin subtype B receptors (ETBR)-mediated diuresis and natriuresis in obese Zucker rats is unclear. METHODS: Lean and obese Zucker rats were exercised or placed on a nonmoving treadmill for 8 weeks. Blood pressure was measured by tail-cuff plethysmography, and functions of AT1R and ETBR in the kidney were measured by natriuresis, respectively. RESULTS: Our data showed that exercise training improved glucose and lipid metabolism, renal function and sodium excretion in obese Zucker rats, accompanied by decreased oxidative stress and GRK4 expression in obese Zucker rats. Moreover, exercise training reduced the Candesartan-induced an increase in diuresis and natriuresis and increased ETBR agonists (BQ3020)-mediated diuresis and natriuresis in obese Zucker rats, which were associated with decreased renal AT1R expression and ETBR phosphorylation levels. CONCLUSIONS: The results demonstrate that exercise training lowers blood pressure via improving renal AT1R and ETBR function through modulating GRK4 expression in Obese Zucker Rats and provides potentially effective targets for obesity-related hypertension.

Platelet-to-Lymphocyte Ratio (PLR), Neutrophil-to-Lymphocyte Ratio (NLR), Monocyte-to-Lymphocyte Ratio (MLR), and Eosinophil-to-Lymphocyte Ratio (ELR) as Biomarkers in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD).

Purpose: The study comprehensively evaluated the prognostic roles of the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), basophil-to-lymphocyte ratio (BLR), and eosinophil-to-lymphocyte ratio (ELR) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Patients and Methods: Six hundred and nineteen patients with AECOPD and 300 healthy volunteers were retrospectively included into the study. The clinical characteristics of the patients with AECOPD and the complete blood counts (CBCs) of the healthy volunteers were collected. The associations of PLR, NLR, MLR, BLR, and ELR with airflow limitation, hospital length of stay (LOS), C-reactive protein (CRP), and in-hospital mortality in patients with AECOPD were analyzed. Results: Compared with the healthy volunteers, PLR, NLR, MLR, BLR, and ELR were all elevated in COPD patients under stable condition. PLR, NLR, MLR, and BLR were further elevated while ELR was lowered during exacerbation. In the patients with AECOPD, PLR, NLR, and MLR were positively correlated with hospital LOS as well as CRP. In contrast, ELR was negatively correlated with hospital LOS as well as CRP. Elevated PLR, NLR, and MLR were all associated with more severe airflow limitation in AECOPD. Elevated PLR, NLR, and MLR were all associated with increased in-hospital mortality while elevated ELR was associated with decreased in-hospital mortality. Binary logistic regression analysis showed that smoking history, FEV1% predicted, pneumonia, pulmonary heart disease (PHD), uric acid (UA), albumin, and MLR were significant independent predictors ofin-hospital mortality. These predictors along with ELR were used to construct a nomogram for predicting in-hospital mortality in AECOPD. The nomogram had a C-index of 0.850 (95% CI: 0.799-0.901), and the calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) further demonstrated its good predictive value and clinical applicability. Conclusion: In summary, PLR, NLR, MLR, and ELR served as useful biomarkers in patients with AECOPD.

Long-Term Prognostic Factors in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A 15-Year Multicenter Retrospective Study.

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a multisystem autoimmune disease with small-vessel involvement. In AAV, microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are major clinicopathologic variants. In addition, myeloperoxidase (MPO) and proteinase 3 (PR3) are major target antigens. The objective of the study was to explore the predictive factors for long-term survival in AAV patients. Materials and Methods: A multicenter retrospective study was carried out on 407 patients between 2005 and 2020. Clinical parameters were obtained from laboratory tests including the ANCA types, antinuclear antibody (ANA), extractable nuclear antigen (ENA), anti-streptolysin O (ASO), glomerular filtration rate (GFR), and the laboratory examinations for the blood routine, liver function, renal function, and immunity, etc. The data for clinical parameters were collected from electronic medical records (EMRs), and the data for patient survival were acquired through regular follow-up. The association of clinical parameters with overall survival (OS) along with 3-year and 5-year survival rates was analyzed, and the nomogram as a predictive model was established according to the analysis results. Results: In the present study, 336 (82.6%) patients and 46 (11.3%) patients were diagnosed with MPA and GPA, respectively. The mean and median OS for all the patients were 2,285 and 2,290 days, respectively. The 1-year, 3-year, 5-year, and 10-year cumulative survival rates for all the patients were 84.2%, 76.3%, 57.2%, and 32.4%, respectively. Univariate and multivariate survival analyses indicated that the independent prognostic factors included age, pathological categories (MPA, GPA, and other types), serum ANCA types (negative or positive for MPO and/or PR3), ANA, ASO, GFR, lymphocyte, neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP), and these clinical parameters except for ASO were used to construct a nomogram. The nomogram for 3-year and 5-year survival rates had a C-index of 0.721 (95% CI 0.676-0.766). The calibration curves showed that the predicted values of the nomogram for 3-year and 5-year survival rates were generally consistent with practical observed values, and decision curve analysis (DCA) further demonstrated the practicability and accuracy of the predictive model. Conclusion: Laboratory tests at diagnosis have great significance in the prediction of long-term survival in AAV patients.

Small RNA deep sequencing reveals novel miRNAs in peripheral blood mononuclear cells from patients with IgA nephropathy.

Peripheral blood mononuclear cells (PBMCs) contribute to the deposition of immunoglobulin A (IgA) and progression of IgA nephropathy (IgAN). This study was performed to identify novel microRNAs (miRNAs/miRs) associated with IgAN. Small RNAs were isolated from PBMCs collected from 10 healthy participants and 10 patients with IgAN; the RNAs were then subjected to high­throughput small RNA sequencing. The results showed that miRNAs constituted 70.33 and 69.83% of small RNAs in PBMCs from healthy participants and patients with IgAN, respectively. In total, 44 differentially expressed miRNAs were identified, of which 34 were upregulated and 10 were downregulated. Among these differentially expressed miRNAs, most showed novel associations with IgAN, except miR­148a­3p, miR­184 and miR­200a. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the target genes of the differentially expressed miRNAs were primarily enriched in cancer pathways, the PI3K­Akt signaling pathway and MAPK pathways, all of which control cell proliferation and gene expression. Moreover, miR­3121­3p, miR­203a­3p and miR­200a­3p may regulate core 1 synthase, glycoprotein­N­acetylgalactosamine 3­ß­galactosyltransferase 1 (C1GALT1) expression by binding to its 3' untranslated region. In conclusion, 44 differentially expressed miRNAs were discovered, 41 of which were newly found to be associated with IgAN. The differentially expressed miRNAs may regulate the progression of IgAN by controlling the behavior of PBMCs or deposition of IgA via targeting of signaling pathways or expression of C1GALT1. These findings may provide a basis for further research regarding IgAN diagnosis and therapy.

MicroRNA-27a-3p directly targets FosB to regulate cell proliferation, apoptosis, and inflammation responses in immunoglobulin a nephropathy.

Immunoglobulin A nephropathy (IgAN) constitutes the most common primary glomerulonephritis worldwide; however, the exact pathogenesis of IgAN is unknown. Previous genome-wide analysis of microRNA (miRNA) expression in the kidney has confirmed that miRNAs are closely related to the pathological changes of IgAN. Accordingly, in this study we found that miR-27a-3p is upregulated in IgAN kidney tissues in addition to human podocytes and tubule epithelial HK2 but not mesangial cells. Methylthiazolyldiphenyl-tetrazolium bromide (MTT), flow cytometry, real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assays were used to verify the regulatory effects of miR-27a-3p and its inhibition on cell proliferation, apoptosis, and release of inflammatory factors in podocytes and HK2 cells. The target genes of miR-27a-3p were predicted using bioinformatics software; the identity of FosB as a target gene of miR-27a-3p was confirmed by luciferase report assay and western blot. Overall, our findings demonstrated that miR-27a-3p regulates cell apoptosis, cell proliferation, and the release of inflammatory cytokines of human podocytes and HK2 cells by directly targeting FosB. Our results therefore suggested that miR-27a-3p might be associated with the pathophysiology of IgAN and may represent a potential target for further studies related to IgAN mechanism or therapeutics.

Effect of Sanqi Oral Liquid on the expressions of CD4⁺, CD8⁺ and CD68⁺ cells in 5/6 nephrectomized rats with chronic renal failure.

OBJECTIVE: To explore the mechanisms of Chinese herbal medicine Sanqi Oral Liquid, composed of Astragalus membranaceus and Panpax notoginseng, in alleviating renal injury by observing its effect on the expressions of CD4(+), CD8(+) and CD68(+) cells in 5/6 nephrectomized rats with chronic renal failure. METHODS: A total of 102 SD rats were randomly divided into six groups: three treatment groups were administrated with high, medium and low dosage of Sanqi Oral Liquid respectively by gavage; a normal group, a 5/6 nephrectomized model group, and a group treated with coated aldehyde oxygenstarch were used as controls. Following oral administration of Sanqi Oral Liquid for 12 weeks, the general condition and renal pathological changes were observed, and the renal function, platelet count (PLT) and the expressions of CD4(+), CD8(+) and CD68(+) cells were determined for each group. RESULTS: There were proliferation of mesangial matrix, renaltubularnecrosis and obvious tubulointerstitial fibrosis in the model group, and they were much milder in the treatment groups. Compared with the model group, the amounts of blood urea nitrogen (BUN), serum creatinine (Scr) and PLT in the treatment groups decreased (P<0.05 for all); and in the group administrated of medium dosage of Sanqi Oral Liquid, the expression of CD4(+) cells was up-regulated and those of CD8(+) and CD68(+) cells were down-regulated (P<0.05 for all), leading to an increased ratio of CD4(+)/CD8(+)(P<0.01). CONCLUSION: Sanqi Oral Liquid has a significant effect on regulating lymphocyte subsets, reducing the infiltration of macrophages in renal tissues and alleviating tubulointerstitial fibrosis, and this may be one of mechanisms of Sanqi Oral Liquid in delaying the progression of chronic kidney diseases.

[Effect of hemodialysis with Chinese herbs of supplementing qi and activating blood circulation on platelet membranous glycoprotein CD62P in patients with chronic renal failure].

OBJECTIVE: To explore the effects of dialysate contained Chinese herbs for replenishing qi and activating blood circulation on platelet membranous glycoprotein CD62P in patients with chronic renal failure (CRF) undergoing hemodialysis. METHODS: Forty patients underwent maintaining hemodialysis were randomly assigned to two groups, the Western medicated group (WMG) and the Chinese herbs group (CHG). The content of CD62P in all patients was detected by ELISA before and after hemodialysis. RESULTS: The levels of blood urea nitrogen, creatinine, potassium, hematocrit, platelet count and carbon dioxide combining power (CO2CP) as well as the expression of CD62P after treatment were significantly changed in both groups with significant difference as compared with those before treatment (both P < 0.05). And comparison between the two groups in expression of CD62P after treatment also showed significant difference (P < 0.05). But the improvement in TCM syndrome between the two groups was insignificantly different (P > 0.05). CONCLUSION: Hemodialysis with dialysate containing Chinese herbs of replenishing qi and activating blood circulation can decrease the expression of platelet membranous glycoprotein CD62P, which may be associated with the mechanism of Chinese herbs in treating CRF.