LCZ696, an angiotensin receptor-neprilysin inhibitor, ameliorates epithelial-mesenchymal transition of peritoneal mesothelial cells and M2 macrophage polarization.

AIMS: To investigate the effects and mechanisms of LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNI), on epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells and on macrophage M2 polarization. METHODS: We examined the effects of LCZ696 in a 4.25% high glucose peritoneal dialysis fluid (PDF)-induced peritoneal fibrosis (PF) mouse model, and explored the mechanisms of LCZ696 on human peritoneal mesothelial cells (HPMCs) stimulated by TGF-ß1 (5 ng/mL) and on Raw264.7 cells stimulated by IL-4 (10 ng/mL). To further elucidate the mechanism, we treated HPMCs with the conditioned medium of Raw264.7 cells. RESULTS: LCZ696 effectively improved PF and inhibited the process of EMT in PDF mice. In vitro, LCZ696 also significantly alleviated the EMT of TGF-ß1 induced HPMCs, although there was no statistically significant difference when compared to the Valsartan treatment group. Moreover, LCZ696 ameliorates the increased expression of Snail and Slug, two nuclear transcription factors that drive the EMT. Mechanistically, TGF-ß1 increased the expression of TGFßRI, p-Smad3, p-PDGFRß and p-EGFR, while treatment with LCZ696 abrogated the activation of TGF-ß/Smad3, PDGFRß and EGFR signaling pathways. Additionally, exposure of Raw264.7 to IL-4 results in increasing expression of Arginase-1, CD163 and p-STAT6. Treatment with LCZ696 inhibited IL-4-elicited M2 macrophage polarization by inactivating the STAT6 signaling pathway. Furthermore, we observed that LCZ696 inhibits EMT by blocking TGF-ß1 secretion from M2 macrophages. CONCLUSION: Our study demonstrated that LCZ696 improves PF and ameliorates TGF-ß1-induced EMT of HPMCs by blocking TGF-ß/Smad3, PDGFRß and EGFR pathways. Meanwhile, LCZ696 also inhibits M2 macrophage polarization by regulating STAT6 pathway.

Megalin-targeting and ROS-responsive elamipretide-conjugated polymeric prodrug for treatment of acute kidney injury.

Acute kidney injury (AKI) is associated with both kidney function loss and increased mortality. In the pathological progression of ischemia-reperfusion-induced AKI, the surge of reactive oxygen species (ROS) plays a crucial role. To combat this, mitochondrial-targeted antioxidant therapy shows great promise as mitochondria are the primary source of ROS in AKI. However, most strategies aiming to target mitochondria directly result in nanodrugs that are too large to pass through the glomerular system and reach the renal tubules, which are the main site of damage in AKI. This study focused on synthesizing a Megalin receptor-targeted polymeric prodrug, low molecular weight chitosan-thioketal-elamipretide (LMWC/TK/Ela), to mitigate excessive ROS in renal tubular epithelial cells for AKI. This soluble polymeric prodrug has the ability to successfully reach the tubular site by crossing the glomerular barrier. Once there, it can responsively release elamipretide, which possesses excellent antioxidative properties. Therefore, this research offers a novel approach to actively target renal tubular epithelial cells and intracellular mitochondria for the relief of AKI.

Megalin-targeted acetylcysteine polymeric prodrug ameliorates ischemia-reperfusion-induced acute kidney injury.

Acute kidney injury (AKI), a condition associated with reactive oxygen species (ROS), causes high mortality in clinics annually. Active targeted antioxidative therapy is emerging as a novel strategy for AKI treatment. In this study, we developed a polymeric prodrug that targets the highly expressed Megalin receptor on proximal tubule cells, enabling direct delivery of N-Acetylcysteine (NAC) for the treatment of ischemia reperfusion injury (IRI)-induced AKI. We conjugated NAC with low molecular weight chitosan (LMWC), a biocompatible and biodegradable polymer consisting of glucosamine and N-acetylglucosamine, to enhance its internalization by tubular epithelial cells. Moreover, we further conjugated triphenylphosphonium (TPP), a lipophilic cation with a delocalized positive charge, to low molecular weight chitosan-NAC in order to enhance the distribution of NAC in mitochondria. Our study confirmed that triphenylphosphonium-low molecular weight chitosan-NAC (TLN) exhibits remarkable therapeutic effects on IRI-AKI mice. This was evidenced by improvements in renal function, reduction in oxidative stress, mitigation of pathological progress, and decreased levels of kidney injury molecule-1. These findings suggested that the polymeric prodrug TLN holds promising potential for IRI-AKI treatment.

Serum sclerostin in vascular calcification in CKD: a meta-analysis.

Vascular calcification (VC) is recognized as a predictor of all-cause and CVD mortality in chronic kidney disease (CKD). VC in CKD is possibly associated with serum sclerostin. The study systematically investigated the role of serum sclerostin in VC in CKD. Following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols, a systematic search was performed of the PubMed, Cochrane Library, and EMBASE databases from inception to 11 November 2022, to identify relevant eligible studies. The data were retrieved, analyzed, and summarized. The hazard ratios (HRs) and odds ratios (ORs) with their corresponding confidence intervals (CIs) were derived and pooled. Thirteen reports (3125 patients) met the inclusion criteria and were included. Sclerostin was associated with the presence of VC (pooled OR = 2.75, 95%CI = 1.81-4.19, p < 0.01) and all-cause mortality (pooled HR = 1.22, 95%CI = 1.19-1.25, p < 0.01) among patients with CKD, but with a decreased risk of cardiovascular events (HR = 0.98, 95%CI = 0.97-1.00, p = 0.02). This meta-analysis suggests that serum sclerostin is associated with VC and all-cause mortality among patients with CKD.

Association of serum klotho levels with different-staged vascular calcification status in patients with maintenance hemodialysis.

BACKGROUND: Vascular calcification (VC) is suggested to be associated with serum klotho levels in patients with maintenance hemodialysis (MHD), whereas there is a lack of reports on the associations of VC status in whole arteries with serum klotho contents. METHODS: One hundred forty eligible patients with MHD and a total of age-and gender-matched normal controls (NCs) were recruited. We analyzed the VC statuses of large arteries and peripheral muscular arteries by calculating the sum of scores from each artery. The levels of serum klotho were determined by ELISA. In addition, the relationship between serum klotho and VC status was evaluated using correlation analysis and regression analysis. RESULTS: The VC severity in MHD patients tended to be worse in comparison with NCs. Serum klotho level in patients with MHD was lower than that in the NC subjects (​P < 0.0001), which was correlated with VC scores as reflected by correlation analysis and regression analysis. Serum klotho concentrations exhibited a dynamic decline along with increased VC status stages. Subjects with higher levels of serum klotho had a higher prevalence of cardiovascular events. CONCLUSION: Our study indicates serum klotho is strongly associated with VC status in a stage-dependent manner.

Comprehensive analysis of prognostic immune-related genes in the tumor microenvironment of hepatocellular carcinoma (HCC).

ABSTRACT: Growing evidence supports that the tumor microenvironment plays a key role in the development and progression of tumors. But immune microenvironment of hepatocellular carcinoma (HCC) has not yet been fully explored. In the present investigation, the clinical value and prognostic significance of immune-related genes in HCC were investigated.The immune and stromal scores of HCC were calculated through the application of Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data Algorithm based on the Cancer Genome Atlas database. Differentially expressed genes were identified using the "edgeR" package of the R software. Functional annotation and pathway enrichment were performed using "ggplots2" and "clusterProfiler" packages in R software. Protein-protein interaction network was constructed using STRING, and the hub genes were identified through the Cytoscape. Survival analysis was performed using Kaplan-Meier methods. Tumor Immune Estimation Resource algorithm was used to view the immune landscape of the microenvironment in HCC.Firstly, the immune and stromal scores of HCC were calculated and we found that the immune and stromal scores of HCC were closely related to the patients' prognosis. Then the differentially expressed genes were identified respectively stratified by the median value of the immune and stromal scores, and the immune-related genes that related to the prognosis in HCC patients were further identified. Functional enrichment analysis and protein-protein interaction networks further showed that these genes mainly participated in immune-related biological process. In addition, dendritic cells were found to be the most abundant in the microenvironment of HCC through Tumor Immune Estimation Resource algorithm and were significantly associated with the patients' prognosis. To robust the results, the immune-related genes were validated in an independent dataset from the Gene Expression Omnibus database.We arrived at a more comprehensive understanding of the microenvironment of HCC and extracted 7 immune-related genes that were significantly associated with the recurrence survival of HCC.

Ellagic acid protects rats from chronic renal failure via MiR-182/FOXO3a axis.

Studies showed that ellagic acid (EA) can significantly improve kidney function, but the renal-protective effects of EA and the potential mechanism require adequate elucidation. This study investigated the mechanisms of EA in chronic renal failure (CRF) injury. A rat model of CRF was established by 5/6 nephrectomy. The body weight, urine volume and urine protein content of the rat model of CRF with EA treatment (0/20/40 mg/kg/day) were recorded. Hematoxylin&eosin (H&E) staining, Masson staining and TUNEL were used for histopathological observation. Serum levels of creatinine value, blood urea nitrogen, superoxide dismutase, glutathione, malondialdehyde, tumor necrosis factor-α, interleukin-6 and intercellular cell adhesion molecule-1 were determined using enzyme-linked immunosorbent assay (ELISA) kits. The expressions of genes involved in CRF damage were detected by quantitative real-time PCR (qRT-PCR) and western blot. The relationships among EA, miR-182 and FOXO3a were verified by TargetScan 7.2, dual-luciferase assay and rescue experiments. In this study, EA treatment significantly increased the body weight, but reduced urination and urine protein content, renal tissue damage, collagen deposition, inflammation and the contents of serum creatinine (Scr), blood urea nitrogen (BUN), and malondialdehyde (MDA), and improved the antioxidant capacity of CRF rats. Moreover, EA treatment inhibited miR-182, TGF-ß1, fibronectin and Bax levels, and promoted those of FOXO3a and Bcl-2 in CRF rats. Additionally, miR-182 specifically targeted FOXO3a, and effectively reduced the renal-protective effect of EA. Further research found that overexpressed FOXO3a partially reversed the inhibitory effect of miR-182 on CRF rats. Our results suggest that EA might reduce CRF injury in rats via miR-182/FOXO3a.

Efficacy and safety of intermittent vs continuous furosemide for heart failure concomitant renal dysfunction: A protocol for systematic review and meta-analysis.

BACKGROUND: Currently, there are no meta-analyses evaluating the efficacy and safety of intermittent vs continuous furosemide for heart failure concomitant renal dysfunction. Our protocol is conceived to evaluate the efficacy and safety of intermittent vs continuous furosemide for heart failure concomitant renal dysfunction. METHODS: We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines and the recommendations of the Cochrane Collaboration to conduct this meta-analysis. The systematic review protocol has been registered in Open Science Framework registries. The following databases including PubMed, Cochrane Library, Web of Science, and EMBASE will be searched using the key phrases "loop diuretics," "furosemide," "heart failure," and "renal dysfunction" for all randomized clinical trials (RCTs) published up to May 2021. Revman 5.3 (Nordic Cochrane Centre, Denmark) will be used to complete the meta-analysis and generate forest plots. We will choose between a fixed effects and random effects model based upon the heterogeneity of included studies. Significance will be set at P < .05. RESULTS: Our protocol is conceived to test the hypothesis that continuous furosemide could lead to better outcomes in patients presenting with heart failure concomitant renal dysfunction. REGISTRATION NUMBER: 10.17605/OSF.IO/CQZRS.

Expression and clinical significance of thrombospondin-1 and plasminogen activator inhibitor-1 in patients with mesangial proliferative glomerulonephritis.

BACKGROUND: As a common pathological type of glomerular disease in China, mesangial proliferative glomerulonephritis is related to plasminogen activator inhibitor-1 (PAI-1) and thrombospondin-1 (TSP-1). Here, this study aims to investigate the expression and clinical significance of TSP-1 and PAI-1 in patients with mesangial proliferative glomerulonephritis. METHODS: Renal tissue specimens from 46 patients with mesangial proliferative glomerulonephritis admitted to this hospital were selected as the subjects, and 8 specimens of renal tissue from autopsy were used as controls. The expression levels of TSP-1 and PAI-1 were detected by immunohistochemistry and analyzed. RESULTS: The 24-hour urine protein, triglyceride, and total cholesterol levels of patients with severe mesangial hyperplasia were significantly higher than those of patients with mild and moderate mesangial hyperplasia, and serum albumin was lower than that of patients with mild and moderate mesangial hyperplasia (P<0.05). The 24-hour urine protein level of patients with moderate mesangial hyperplasia was higher than that of patients with mild mesangial hyperplasia while the albumin level was lower (P<0.05), but there was no significant difference in triglyceride and total cholesterol (P>0.05). There was no significant difference in creatinine clearance (Ccr) between the three groups (P>0.05).The 24-hour urine protein and urine alpha-1-microglobulin (A1M) levels in patients with renal interstitial disease were higher than those in patients without renal interstitial disease, while their Ccr level was lower (P<0.05). TSP-1 and PAI-1 were not positively expressed in the glomeruli and renal tubules of specimens of the control group. However, in mesangial hyperplasia patients, the expression of TSP-1 and PAI-1 in mesangial hyperplasia with varying degrees and in different renal tubular damage were as follows: mild degree < moderate degree < severe degree (P<0.05). CONCLUSIONS: The pathological changes of mesangial proliferative glomerulonephritis are related to 24- hour urine protein, triglyceride, total cholesterol level, urine A1M, and Ccr level. The expression of TSP1 and PAI-1 in the mesenchyme of glomerular and renal tubules significantly increased with the severity of the disease, suggesting that TSP-1 and PAI-1 play an important role in the occurrence and development of mesangial proliferative glomerulonephritis.

WITHDRAWN: Analysis of Infection Factors and Nerve Conduction Velocity in Patients with Chronic Glomerular Disease Based on Information Health Data and Electromyography.

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Pseudo-acute Renal Failure due to Intraperitoneal Urine Leakage.

Ascites, oliguria and vomiting with an increasing serum creatinine level are often observed in patients with acute renal failure. However, these symptoms are also noted in individuals with intraperitoneal urinary leakage. Bladder rupture without a history of obvious trauma is sometimes mistaken for acute renal failure. We herein report a case of bladder perforation resembling acute renal failure in which the presentation was delayed until the patient began to experience symptoms of urinary ascites. The diagnostic dilemma associated with the rarity of this condition and possible aetiologies are discussed.

Expression of both matrix metalloproteinase-2 and its tissue inhibitor-2 in tunica media of radial artery in uremic patients.

OBJECTIVE: To investigate the expression and clinical significance of both matrix metalloproteinase-2 (MMP-2) and its tissue inhibitor (tissue inhibitor of metalloproteinase-2 (TIMP-2)) in tunica media of radial artery in uremic patients. METHODS: The modified radial arteries from 80 uremic patients during internal arteriovenous fistula surgery were selected and used as experimental specimens. The calcification of tunica media was observed by alizarin red staining, and the expression status of MMP-2, TIMP-2, osteoprotegerin (OPG), and osteopontin (OPN) in tunica media of radial arteries of these patients was detected by immunohistochemical method. The semiquantitative analysis and comparison were conducted based on the calcification grading and the expression of each test protein in tunica media of radial artery. RESULTS: Of the 80 cases of radial artery specimens, 37 cases were presented with various degrees of calcification of tunica media, and the calcification rate was 46.25%; the expression of MMP-2, TIMP-2, OPG, and OPN could be detected in the calcificated tunica media of the radial artery and was positively correlated with the degree of vascular calcification (p < 0.05). CONCLUSION: The incidence of vascular calcification in uremic patients was high. The occurrence of calcification in tunica media of the radial artery was correlated with the expression of MMP-2 and TIMP-2.