ABSTRACT
Background: Immunoglobulin A nephropathy (IgAN) with podocytopathy is a rare pathological type of glomerular disease. The use of rituximab (RTX) in the treatment of glomerular diseases has increased in recent decades, but the efficacy of RTX in the treatment of patients with IgAN and podocytopathy has rarely been reported. Methods: This was a single-centre retrospective study of IgAN patients with podocytopathy who were treated with RTX as second-line therapy was conducted at our centre from 2019 to 2022. The aim of this study was to investigate the efficacy and safety of RTX in IgAN patients with podocytopathy. Results: Seven out of eight patients met the criteria for complete remission following RTX therapy. Only one patient experienced adverse events (infectious diarrhoea and pulmonary infection) and experienced relapse 6 months after RTX therapy. The maximum relapse-free time after RTX therapy was 20 months, while the maximum relapse-free time before RTX therapy was only 6 months. The number of relapses before RTX therapy (per year) was one to four; moreover, seven patients did not relapse and maintained remission at the last follow-up despite steroid withdrawal after RTX therapy. Conclusion: Overall, RTX effectively reduced proteinuria, increased the maximum relapse-free time, reduced the number of relapses per year and helped patients stop steroid use as soon as possible. RTX also helped most patients achieve clinical remission. RTX appears to be an effective and safe alternative for treating IgAN patients with podocytopathy with steroid dependence or frequent relapse.
ABSTRACT
Hypoxia-induced inflammation and apoptosis are important pathophysiological features of heat stroke-induced acute kidney injury (HS-AKI). Hypoxia-inducible factor (HIF) is a key protein that regulates cell adaptation to hypoxia. HIF-prolyl hydroxylase inhibitor (HIF-PHI) stabilizes HIF to increase cell adaptation to hypoxia. Herein, we reported that HIF-PHI pretreatment significantly improved renal function, enhanced thermotolerance, and increased the survival rate of mice in the context of HS. Moreover, HIF-PHI could alleviate HS-induced mitochondrial damage, inflammation, and apoptosis in renal tubular epithelial cells (RTECs) by enhancing mitophagy in vitro and in vivo. By contrast, mitophagy inhibitors Mdivi-1, 3-MA, and Baf-A1 reversed the renoprotective effects of HIF-PHI. Mechanistically, HIF-PHI protects RTECs from inflammation and apoptosis by enhancing Bcl-2 adenovirus E18 19-kDa-interacting protein 3 (BNIP3)-mediated mitophagy, while genetic ablation of BNIP3 attenuated HIF-PHI-induced mitophagy and abolished HIF-PHI-mediated renal protection. Thus, our results indicated that HIF-PHI protects renal function by upregulating BNIP3-mediated mitophagy to improve HS-induced inflammation and apoptosis of RTECs, suggesting HIF-PHI as a promising therapeutic agent to treat HS-AKI.
Subject(s)
Acute Kidney Injury , Heat Stroke , Membrane Proteins , Mitophagy , Prolyl-Hydroxylase Inhibitors , Animals , Male , Mice , Acute Kidney Injury/drug therapy , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Acute Kidney Injury/etiology , Apoptosis/drug effects , Heat Stroke/complications , Heat Stroke/drug therapy , Heat Stroke/metabolism , Membrane Proteins/metabolism , Membrane Proteins/genetics , Mice, Inbred C57BL , Mitochondrial Proteins/metabolism , Mitochondrial Proteins/genetics , Mitophagy/drug effects , Prolyl-Hydroxylase Inhibitors/pharmacology , Prolyl-Hydroxylase Inhibitors/therapeutic useABSTRACT
BACKGROUND: The incidence of chronic kidney disease among patients with diabetes mellitus (DM) remains a global concern. Long-term obesity is known to possibly influence the development of type 2 diabetes mellitus. However, no previous meta-analysis has assessed the effects of body mass index (BMI) on adverse kidney events in patients with DM. AIM: To determine the impact of BMI on adverse kidney events in patients with DM. METHODS: A systematic literature search was performed on the PubMed, ISI Web of Science, Scopus, Ovid, Google Scholar, EMBASE, and BMJ databases. We included trials with the following characteristics: (1) Type of study: Prospective, retrospective, randomized, and non-randomized in design; (2) participants: Restricted to patients with DM aged ≥ 18 years; (3) intervention: No intervention; and (4) kidney adverse events: Onset of diabetic kidney disease [estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2 and/or microalbuminuria value of ≥ 30 mg/g Cr], serum creatinine increase of more than double the baseline or end-stage renal disease (eGFR < 15 mL/min/1.73 m2 or dialysis), or death. RESULTS: Overall, 11 studies involving 801 patients with DM were included. High BMI (≥ 25 kg/m2) was significantly associated with higher blood pressure (BP) [systolic BP by 0.20, 95% confidence interval (CI): 0.15-0.25, P < 0.00001; diastolic BP by 0.21 mmHg, 95%CI: 0.04-0.37, P = 0.010], serum albumin, triglycerides [standard mean difference (SMD) = 0.35, 95%CI: 0.29-0.41, P < 0.00001], low-density lipoprotein (SMD = 0.12, 95%CI: 0.04-0.20, P = 0.030), and lower high-density lipoprotein (SMD = -0.36, 95%CI: -0.51 to -0.21, P < 0.00001) in patients with DM compared with those with low BMIs (< 25 kg/m2). Our analysis showed that high BMI was associated with a higher risk ratio of adverse kidney events than low BMI (RR: 1.22, 95%CI: 1.01-1.43, P = 0.036). CONCLUSION: The present analysis suggested that high BMI was a risk factor for adverse kidney events in patients with DM.
ABSTRACT
Streptococcal infection is a common cause of acute glomerulonephritis. Cardiac damage associated with streptococcal infection commonly occurs in acute rheumatic fever. However, cases of acute non-rheumatic streptococcal myocarditis have been reported in recent years. We report a novel case of concurrent acute glomerulonephritis and non-rheumatic myocarditis following streptococcal infection. A good prognosis was achieved with antibiotic and immunosuppressive therapy, indicating that Streptococcus causes cardiorenal syndrome type 5 via an immune-mediated response. A better understanding of post-streptococcal cardiorenal syndrome is warranted to enable the early diagnosis and treatment of affected patients.
Subject(s)
Cardio-Renal Syndrome , Glomerulonephritis , Myocarditis , Rheumatic Heart Disease , Streptococcal Infections , Humans , Myocarditis/complications , Cardio-Renal Syndrome/complications , Streptococcal Infections/complications , Streptococcal Infections/diagnosis , Rheumatic Heart Disease/complications , Glomerulonephritis/complications , Glomerulonephritis/diagnosis , Acute Disease , Streptococcus pyogenesABSTRACT
Hemophagocytic syndrome (HPS) is a proliferative disease of the mononuclear macrophage system involving multiple organs and systems. We report a 50-year-old Asian woman who presented with unexplained fever and proteinuria. Laboratory tests showed cytopenia, considerably elevated serum ferritin and IL-2 receptor concentrations, and evidence of hemophagocytosis in the bone marrow. A renal biopsy showed macrophage infiltration into the glomerulus, resulting in podocyte and endothelial cell damage. We finally diagnosed the patient with extranodal natural killer/T-cell lymphoma, nasal type that induced HPS-related histiocytic glomerulopathy. Proteinuria and inflammation responded to treatment with high-dose pulsed methylprednisolone combined with VP-16 and cyclosporine. To the best of our knowledge, this is the first documented case of HPS-related histiocytic glomerulopathy triggered by a malignant tumor.
Subject(s)
Lymphohistiocytosis, Hemophagocytic , Lymphoma, T-Cell , Female , Humans , Middle Aged , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Macrophages , Cyclosporine , Killer Cells, NaturalABSTRACT
Canonical transient receptor potential-6 (TRPC6) has been reported to be involved in cell damage after ischemia/reperfusion (I/R) injury in target organs. While the effect and of TRPC6 on pyroptosis in renal I/R injury remain unclear. In our study, we first established the renal I/R mouse model and oxygen-glucose deprivation and re-oxygenation (OGD/R) cell model, and investigated the impacts of TRPC6 on the pyroptosis-related proteins using CCK-8, western blot, ELISA, and immunofluorescence probes. Besides, we also explored the mechanism of TRPC6 in pyroptosis of renal tubular epithelial cells through A20 knockdown or overexpression and zinc chloride (ZnCl2 ) or a zinc ion chelator (TPEN) treatment. Our results indicated that I/R injury could cause downregulation of TRPC6 both in vivo and in vitro. In the I/R injury murine model, TRPC6 inhibition exacerbated tissue damage and upregulated NLRP3, ASC, caspase-1, IL-18, and IL-1ß, which could be alleviated by the administration of ZnCl2 . In the OGD/R cell model, inhibitor of TRPC6 (SAR7334) reduced zinc ion influx, aggravated cell death and upregulated pyroptosis-related protein. The pyroptosis phenotype also could be alleviated by ZnCl2 and intensified by TPEN. Overexpression of A20 reduced the expression of pyroptosis-related protein, increased cell viability in the sh-TRPC6 and TPEN-treated OGD/R cell models, while A20 deficiency impaired the protective effect of zinc ion. Therefore, our results indicate that TRPC6 could promote zinc ion influx in renal tubular epithelial cells, thereby upregulating intracellular A20, inhibiting the activation of inflammasome NLRP3, and ultimately attenuating renal I/R injury.
Subject(s)
Pyroptosis , Reperfusion Injury , Animals , Epithelial Cells , Inflammasomes , Mice , NLR Family, Pyrin Domain-Containing 3 Protein , TRPC6 Cation Channel , ZincABSTRACT
BACKGROUND: Myofibroblast (MF) activation is the key event of irreversible renal interstitial fibrosis. Anoikis resistance is the hallmark of active MFs, which is conferred by continuous activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt) pathway. Our previous study found that tumor-suppressing STF cDNA 3 (TSSC3) enhances the sensitivity of cells to anoikis via the PI3K/Akt pathway. Therefore, we hypothesized that TSSC3 might suppress renal interstitial fibrosis by inducing anoikis via the PI3K/Akt pathway. METHODS: Cell anoikis was induced by the exogenous addition of RGD-containing peptides or by culturing cells in suspension. MFs were established by stimulating HK-2 renal tubular epithelial cells with transforming growth factor beta 1 (TGF-ß1). Lentivirus vectors were to construct a TSSC3 overexpression cell model. The effects of TSSC3 on the anoikis, growth, migration, invasion, and contraction of MFs were determined using annexin V-fluorescein isothiocyanate assays, cell counting kit-8 assays, wound healing migration assays, matrigel invasion assays, and collagen-based contraction assays. RESULTS: The results demonstrated that TGF-ß1, simultaneous with the induction of MF differentiation, confers significant protection against anoikis-induced cell death, which could be partly reversed by treatment with the PI3K/Akt pathway inhibitor, LY294002. Moreover, overexpression of TSSC3 obviously impaired cell growth, cell migration, cell invasion, contraction, and anoikis resistance of MFs, and decreased the activity of the PI3K/Akt pathway and the production of extracellular matrix molecules, all of which could be attenuated by treatment with the PI3K/Akt pathway activator, 740Y-P. Taken together, this study suggested that TSSC3 attenuates the anoikis resistance and profibrogenic ability of TGF-ß1-induced MF by regulating the PI3K-Akt pathway. CONCLUSION: These findings provide a biological basis for further exploration of the therapeutic significance of targeting MF via TSSC3 in renal interstitial fibrosis.
Subject(s)
Anoikis , Nuclear Proteins/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Cell Line , Humans , Nuclear Proteins/genetics , Signal Transduction , Up-RegulationABSTRACT
Renal injury is common in patients with coronavirus disease 2019 (COVID-19). We aimed to determine the relationship of estimated glomerular filtration rate (eGFR) and acute kidney injury (AKI) with the characteristics, progression, and prognosis of COVID-19 in-patients. We retrospectively reviewed 1851 COVID-19 patients admitted to 3 hospitals in Wuhan, China. Clinical, laboratory, radiological, treatment, complication, and outcome data were analyzed. Patients were stratified according to levels of eGFR (≥ 90 vs. 60-89 vs. < 60 mL/min/1.73 m2). The risk of reaching the composite endpoint-intensive care unit admission, invasive ventilation, or death-was compared. On admission, 25.5% patients had renal impairment (eGFR < 90 mL/min/1.73 m2), but only 2.6% patients had chronic kidney disease (CKD). The overall in-hospital AKI incidence was 6.7%. Severe illness and comorbidities (hypertension, diabetes, CKD, and cardiovascular/cerebrovascular diseases) were more common among patients with low eGFR (< 90 mL/min/1.73 m2). Despite the more frequent use of intensive oxygen therapy, continuous blood purification, and glucocorticoid treatment, the prognosis of these patients was unsatisfactory, with the incidence of the composite endpoint (15.4% vs. 19.6% vs. 54.5%; P = 0.000) and complications (AKI, respiratory failure, cardiac injury, coagulation disorders, sepsis, etc.) increasing with decreasing eGFR. Kaplan-Meier survival analysis revealed that patients with eGFR < 90 mL/min/1.73 m2 or AKI had significantly escalated risks of reaching the composite endpoint. Multivariate regression analysis showed that renal insufficiency (eGFR < 60 mL/min/1.73 m2) on admission and in-hospital AKI independently predicted poor prognosis among COVID-19 in-patients. And renal impairment on admission was a greater predictor of poor prognosis in non-elderly patients than that in elderly patients. Early and continuous renal-function monitoring and early AKI diagnosis are necessary to predict and prevent the progression of COVID-19.
Subject(s)
Acute Kidney Injury/complications , COVID-19/complications , Acute Kidney Injury/diagnosis , Acute Kidney Injury/epidemiology , Acute Kidney Injury/therapy , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/therapy , China/epidemiology , Disease Management , Female , Glomerular Filtration Rate , Hospitalization , Hospitals , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Prognosis , Retrospective Studies , SARS-CoV-2/isolation & purificationABSTRACT
BACKGROUND: Accelerated senescence of renal tubular epithelial cells (RTECs) might contribute to immunoglobulin A nephropathy (IgAN) progression. This study aimed to determine whether the RTEC senescence marker, decoy receptor 2 (DcR2), could predict prognosis in IgAN. METHODS: We included a retrospective cohort of 105 patients with biopsy-proven IgAN. Tubular DcR2 expression was assessed at renal biopsy and the Oxford histological MEST-C score [mesangial hypercellularity (M), endocapillary proliferation (E), segmental sclerosis (S), interstitial fibrosis/tubular atrophy (T) and crescents (C)] defined disease severity. IgAN progression was defined as a composite of end-stage renal disease or a 30% decline in the estimated glomerular filtration rate (eGFR), analyzed using Kaplan-Meier and Cox regression analyses. RESULTS: Tubular DcR2 was overexpressed in IgAN. Numbers of DcR2 and p16 double-positive RTECs increased with increasing severity of tubular atrophy/interstitial fibrosis (T lesion). Patients with ≥25% tubular DcR2 expression experienced worse proteinuria, T lesions and a lower eGFR. Cumulative renal survival was significantly lower in patients with ≥25% DcR2 positivity. Multivariate regression analyses showed that ≥25% tubular DcR2 expression was significantly associated with worse eGFR slopes (the rate of renal function decline; P = 0.003) and the incidence of the composite outcome (P = 0.001) in IgAN. The addition of tubular DcR2 to a model with clinical data at biopsy (mean arterial pressure, proteinuria and eGFR) or MEST-C score significantly improved the 5-year risk prediction of IgAN progression, as confirmed by receiver operating characteristic curve analyses. CONCLUSIONS: Tubular DcR2 expression detected at biopsy was a strong independent predictor for IgAN progression and might have prognostic value in addition to established risk markers.
ABSTRACT
BACKGROUND: Even mild renal disease is a powerful cardiovascular risk factor. However, the association between these pathophysiologic processes (especially in the early asymptomatic stage) is not known. METHODS: We recruited 243 asymptomatic patients with Stages 1-4 chronic kidney disease (CKD) without obstructive coronary artery disease (CAD). We distinguished different degrees of severity of intrarenal arterial lesions (IALs) according to the Oxford classification. Myocardial microcirculation perfusion was measured using single-photon emission computed tomography (SPECT). Summed scores of 17 stress and rest image segments produced the summed stress score (SSS) and summed rest score (SRS), respectively. The summed difference score (SDS) was calculated as the difference between the SSS and SRS. Coronary microvascular disease (CMD) was defined as abnormal SPECT (SSS ≥4 or SDS ≥2) in the absence of obstructive CAD. RESULTS: Participants showed a stepwise increase in CMD severity with IAL aggravation. SSS of no/mild/moderate/severe IALs was 1.64 ± 1.08, 2.56 ± 1.35, 4.42 ± 2.17 and 6.48 ± 3.52, respectively (P < 0.05 for all). SDS of no/mild/moderate/severe IALs was 1.29 ± 0.49, 1.75 ± 0.56, 3.06 ± 1.12 and 4.16 ± 1.85, respectively (P < 0.05 for all). The percentage of subclinical CMD in CKD patients with IALs was significantly higher than in those without IALs (69.57% versus 14.71%; P = 0.01). Multiple regression analysis showed that renal arteriolar hyalinization (odds ratio = 1.578, P = 0.009) was associated independently with subclinical CMD. CONCLUSIONS: We demonstrated, for the first time, that impaired perfusion in the myocardial microcirculation in asymptomatic patients with Stages 1-4 CKD with IALs. Renal arteriolar hyalinization may be a useful marker of CMD in CKD.
Subject(s)
Coronary Artery Disease , Myocardial Perfusion Imaging , Renal Insufficiency, Chronic , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/etiology , Humans , Microcirculation , Perfusion , Tomography, Emission-Computed, Single-PhotonABSTRACT
BACKGROUND: Urinary DcR2 (uDcR2) is a biomarker for the early detection the tubulointerstitial injury (TII) in patients with chronic kidney disease (CKD), but the high-dose hook effect may lead to falsely low or even negative results when using an enzyme-linked immunosorbent assay (ELISA). This study aimed to investigate if the high-dose hook effect exists with ELISA testing, and to uncover a potential approach for reducing this effect. METHODS: 72 CKD patients were recruited and categorized into four groups based on TII scores. uDcR2 was measured in undiluted and serially diluted (two-, four-, eight- and 16-fold dilutions) urine using an ELISA kit. The results from the assay were normalized to urinary creatinine. We evaluated the correlation between uDcR2/cre levels at different dilutions and renal histological parameters. Receiver operating characteristic (ROC) curves were generated to examine the value of uDcR2/cre for predicting TII. RESULTS: uDcR2/cre levels in the undiluted urine were significantly higher in patients with CKD than those in the control. However, higher TII scores did not yield higher levels of uDcR2/cre in the undiluted urine. After serial dilution, uDcR2/cre levels were highest with the four-fold dilution. A positive correlation was found between uDcR2/cre levels at different dilutions and TII scores, with the highest correlation coefficient and the largest AUC being observed at the four-fold dilution. CONCLUSIONS: The high-dose hook effect was apparent during ELISA testing of uDcR2 in CKD patients, yet dilution of the urine samples neutralized this effect. However, the use of a four-fold dilution of urine for uDcR2/cre testing may eliminate the high-dose hook effect and make it possible to effectively monitor the severity of TII in CKD patients.
Subject(s)
Renal Insufficiency, Chronic/urine , Tumor Necrosis Factor Decoy Receptors/urine , Aged , Enzyme-Linked Immunosorbent Assay/methods , Female , Humans , Male , Middle Aged , Renal Insufficiency, Chronic/pathology , Severity of Illness IndexABSTRACT
Premature senescence is a key process in the progression of diabetic nephropathy (DN). Premature senescence of renal tubular epithelial cells (RTEC) in DN may result from the accumulation of damaged mitochondria. Mitophagy is the principal process that eliminates damaged mitochondria through PTEN-induced putative kinase 1 (PINK1)-mediated recruitment of optineurin (OPTN) to mitochondria. We aimed to examine the involvement of OPTN in mitophagy regulation of cellular senescence in RTEC in the context of DN. In vitro, the expression of senescence markers P16, P21, DcR2, SA-ß-gal, SAHF, and insufficient mitophagic degradation marker (mitochondrial P62) in mouse RTECs increased after culture in 30 mM high-glucose (HG) conditions for 48 h. Mitochondrial fission/mitophagy inhibitor Mdivi-1 significantly enhanced RTEC senescence under HG conditions, whereas autophagy/mitophagy agonist Torin1 inhibited cell senescence. MitoTempo inhibited HG-induced mitochondrial reactive oxygen species and cell senescence with or without Mdivi-1. The expression of PINK1 and OPTN, two regulatory factors for mitophagosome formation, decreased significantly after HG stimulation. Overexpression of PINK1 did not enhance mitophagosome formation under HG conditions. OPTN silencing significantly inhibited HG-induced mitophagosome formation, and overexpression of OPTN relieved cellular senescence through promoting mitophagy. In clinical specimens, renal OPTN expression was gradually decreased with increased tubulointerstitial injury scores. OPTN-positive renal tubular cells did not express senescence marker P16. OPTN expression also negatively correlated with serum creatinine levels, and positively correlated with eGFR. Thus, OPTN-mediated mitophagy plays a crucial regulatory role in HG-induced RTEC senescence in DN. OPTN may, therefore, be a potential antisenescence factor in DN.
Subject(s)
Cellular Senescence , Cytoprotection , Diabetic Nephropathies/pathology , Epithelial Cells/pathology , Eye Proteins/metabolism , Kidney Tubules/pathology , Mitophagy , Transcription Factor TFIIIA/metabolism , Animals , Cell Cycle Proteins , Disease Progression , Epithelial Cells/metabolism , Epithelial Cells/ultrastructure , Glucose/toxicity , Humans , Membrane Transport Proteins , Mice, Inbred C57BL , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondria/pathology , Mitochondria/ultrastructure , Phagosomes/drug effects , Phagosomes/metabolism , Phagosomes/ultrastructure , Protein Kinases/metabolism , Reactive Oxygen Species/metabolismABSTRACT
Cell senescence plays a major role in the progression of tumors and chronic conditions such as diabetes and chronic kidney disease. Senescent cells are an important model for the study of aging-related diseases, and there is currently no efficient method for sorting out senescent cells. Decoy receptor 2 (DcR2) is a transmembrane receptor of the tumor necrosis factor superfamily, which is specifically expressed in senescent cells. In this study, we used magnetic activated cell sorting (MACS) isolation of a highly-pure populations DcR2-positive renal tubular epithelial cells (RTECs) based on three senescent cell models including the fifth passage cells, advanced glycation end-products (AGEs)- and H2O2-induced cells. The percentages of DcR2 positive RTECs in G1 and S phases increased by 20% and 4%, respectively, as compared to that in the pre-sorted cells. The positivity rates of SA-ß-gal, p16, and senescence-associated heterochromatin foci (SAHF) in DcR2-positive RTECs were about 40%, 30%, and 44% higher than that prior to cell sorting. The levels of IL-6 and TGF-ß1 in the supernatant were increased by 1.7 and 1.5 folds, respectively, as compared to that observed prior to sorting. No significant cell death was observed after 5days of continuous culture. Ki-67 positive expression rate in DcR2 negative RTECs was significantly higher than that in DcR2 positive RTECs after MACS. We demonstrated the use of DcR2 to classify live, senescent RTECs with a high specificity and stability. Our findings lay the foundation for further study of senescent RTECs in the progression of chronic kidney disease.
Subject(s)
Cell Proliferation , Cellular Senescence , Epithelial Cells/immunology , Immunomagnetic Separation , Kidney Tubules/immunology , Tumor Necrosis Factor Decoy Receptors/immunology , Animals , Cell Proliferation/drug effects , Cells, Cultured , Cellular Senescence/drug effects , Epithelial Cells/drug effects , Epithelial Cells/metabolism , G1 Phase Cell Cycle Checkpoints , Glycation End Products, Advanced/pharmacology , Hydrogen Peroxide/pharmacology , Interleukin-6/metabolism , Ki-67 Antigen/metabolism , Kidney Tubules/cytology , Kidney Tubules/drug effects , Kidney Tubules/metabolism , Male , Mice, Inbred C57BL , Phenotype , S Phase Cell Cycle Checkpoints , Time Factors , Transforming Growth Factor beta1/metabolism , Tumor Necrosis Factor Decoy Receptors/metabolismABSTRACT
Tubulointerstitial injury (TII) plays a crucial role in the progression of diabetic nephropathy (DN), but lack of specific and sensitive biomarkers for monitoring TII in DN management. This study is to investigate whether urinary decoy receptor 2 (uDcR2) could serve as a novel noninvasive biomarker for assessing TII in DN. We recruited 311 type 2 diabetics and 139 DN patients who were diagnosed by renal biopsy. uDcR2 levels were measured by ELISA, and renal DcR2 expression was detected immunohistochemically. Associations between uDcR2 and renal DcR2 and renal functional parameters were evaluated. Receiver operating characteristics (ROC) curve analyzed area under the curve (AUC) of uDcR2 for assessing TII. Double staining was undertaken for renal DcR2 with proximal and distal tubular markers; senescent markers p16, p21, and senescence-associated ß-galactosidase (SA-ß-gal); and fibrotic markers collagen I and IV. We found DcR2 was primarily expressed in renal proximal tubules; uDcR2 levels were elevated per albuminuria stratum and correlated with renal functional parameters in diabetics and were associated with percentage of tubular DcR2 and TII score in DN. The uDcR2 had an AUC of 0.909 for assessing TII in DN by ROC analysis. Almost all tubular DcR2 was coexpressed with p16 and p21, and nearly more than one-half of tubular DcR2 was positive for SA-ß-gal, primarily in collagen I- and IV-positive regions of DN. Our results indicate uDcR2 could potentially serve as a novel biomarker for TII and may reflect senescence of renal proximal tubular cells in DN pathogenesis.
Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/urine , Kidney Tubules, Proximal/chemistry , Tumor Necrosis Factor Decoy Receptors/urine , Aged , Area Under Curve , Biomarkers/urine , Biopsy , Case-Control Studies , Cellular Senescence , Collagen Type I/analysis , Collagen Type IV/analysis , Cross-Sectional Studies , Cyclin-Dependent Kinase Inhibitor p16/analysis , Cyclin-Dependent Kinase Inhibitor p21/analysis , Diabetic Nephropathies/diagnosis , Diabetic Nephropathies/etiology , Enzyme-Linked Immunosorbent Assay , Female , Fibrosis , Humans , Immunohistochemistry , Kidney Tubules, Proximal/pathology , Male , Middle Aged , Predictive Value of Tests , ROC Curve , Up-Regulation , Urinalysis , beta-Galactosidase/analysisABSTRACT
Suppression of anoikis is a prerequisite for tumor cell metastasis, which is correlated with chemoresistance and poor prognosis. We characterized a novel interaction between RanBP9 SPRY domain and TSSC3 PH domain by which RanBP9/TSSC3 complex exerts transcription and post-translation regulation in osteosarcoma. RanBP9/TSSC3 complex was inversely correlated with a highly anoikis-resistant phenotype in osteosarcoma cells and metastasis in human osteosarcoma. RanBP9 cooperated with TSSC3 to inhibit anchorage-independent growth and to promote anoikis in vitro and suppress lung metastasis in vivo. Moreover, RanBP9 SPRY domain was required for RanBP9/TSSC3 complex-mediated anoikis resistance. Mechanistically, RanBP9 formed a ternary complex with TSSC3 and Src to scaffold this interaction, which suppressed both Src and Src-dependent Akt pathway activations and facilitated mitochondrial-associated anoikis. Collectively, the newly identified RanBP9/TSSC3 complex cooperatively suppress metastasis via downregulation of Src-dependent Akt pathway to expedite mitochondrial-associated anoikis. This study provides a biological basis for exploring the therapeutic significance of dual targeting of RanBP9 and TSSC3 in osteosarcoma.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Anoikis , Cytoskeletal Proteins/metabolism , Lung Neoplasms/secondary , Nuclear Proteins/metabolism , Osteosarcoma/pathology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , src-Family Kinases/metabolism , Adaptor Proteins, Signal Transducing/chemistry , Adolescent , Adult , Animals , Cell Line, Tumor , Cell Proliferation , Child , Cytoskeletal Proteins/chemistry , Down-Regulation , Female , Humans , Lung Neoplasms/metabolism , Male , Mice, SCID , Mitochondria/metabolism , Models, Biological , Nuclear Proteins/chemistry , Osteosarcoma/enzymology , Phenotype , Protein Binding , Protein Domains , Protein Processing, Post-Translational , Transcription, Genetic , Young AdultABSTRACT
Epithelial to mesenchymal transition (EMT) has received considerable attention as a conceptual paradigm for explaining the invasive and metastatic behavior of cells during cancer progression. Our previous study showed that loss of expression of TSSC3 is positively associated with osteosarcoma malignancy and progression. However, whether TSSC3 mediates EMT in osteosarcoma is poorly understood. In the present study, we determined that TSSC3 downregulation induced cell migration and invasion ability and promoted mesenchymal transition of osteosarcoma cells by upregulating mesenchymal markers and inhibiting the epithelial markers. Furthermore, TSSC3 downregulation elicited a signaling cascade that included increased levels of Wnt3a and LRP5, inactivation of GSK-3ß, accumulation of nuclear ß-catenin and Snail, the augmented binding of ß-catenin to TCF-4, and accordingly increased the expression of Wnt target genes (CD44, MMP7). The gene knockdown of these signaling proteins could inhibit TSSC3 downregulation-promoted EMT, migration, and invasion in osteosarcoma. Finally, TSSC3 overexpression obviously inhibited cell migration, invasion, and repressed mesenchymal phenotypes, reducing lung metastasis through GSK-3ß activation. Collectively, TSSC3 downregulation promotes the EMT of osteosarcoma cells by regulating EMT markers via a signal transduction pathway that involves Snail, Wnt-ß-catenin/TCF, and GSK-3ß.
Subject(s)
Bone Neoplasms/pathology , Epithelial-Mesenchymal Transition , Glycogen Synthase Kinase 3/physiology , Nuclear Proteins/physiology , Osteosarcoma/pathology , Signal Transduction/physiology , Transcription Factors/physiology , beta Catenin/physiology , Animals , Cell Line, Tumor , Cell Movement , Down-Regulation , Female , Glycogen Synthase Kinase 3 beta , Humans , Lung Neoplasms/secondary , Mice , Neoplasm Invasiveness , Snail Family Transcription FactorsABSTRACT
BACKGROUND AND AIMS: Abnormal circadian rhythm of blood pressure (BP) is closely related to target organ damage in hypertension. However, the association between abnormal circadian rhythm of BP and renal injury is not clear. We investigated whether renal injury is associated with nocturnal BP and circadian rhythm of BP in Chinese IgAN patients. METHODS: Clinic and 24 h ambulatory BP monitoring data were obtained from 330 Chinese IgAN patients with mean 24 h BP < 130/80 and mean daytime BP < 135/85 mmHg. Renal histopathological injury was determined according to the Oxford classification of IgAN. RESULTS: Among the 330 IgAN subjects, 35.8% suffered from nocturnal hypertension, 61.5% had abnormal circadian BP, and 27% had nocturnal hypertension with a nondipping pattern. Compared with nocturnal normotensive patients, patients with nocturnal hypertension had significantly higher levels of blood cystatin C, blood uric acid, and lower estimated glomerular filtration rate (eGFR), and significantly a higher mean renal tissue injury score. The nondipping hypertensive group had significantly higher nocturnal diastolic and systolic BP, blood uric acid, and glomerulosclerosis rates, whereas eGFR was lower. In nondipping hypertensive patients, urinary sodium excretion and renal tissue injury scores were significantly higher than dipping patients. Nocturnal hypertension and abnormal circadian BP correlated with renal tissue injury, renal interstitial fibrosis, and aortic arch atherosclerosis. CONCLUSION: Abnormal circadian rhythm of BP and nocturnal hypertension are common clinical manifestations in Chinese IgAN patients with normal mean 24 h BP. Abnormal circadian BP and nocturnal hypertension may accelerate IgAN progression by inducing renal dysfunction and histopathological damage.
Subject(s)
Blood Pressure , Circadian Rhythm , Glomerulonephritis, IGA/pathology , Glomerulonephritis, IGA/physiopathology , Hypertension/complications , Hypertension/physiopathology , Adolescent , Adult , Aorta, Thoracic/pathology , Asian People , Blood Pressure Monitoring, Ambulatory , China , Cystatin C/blood , Disease Progression , Female , Fibrosis/pathology , Glomerular Filtration Rate , Glomerulonephritis, IGA/complications , Humans , Hypertension/pathology , Kidney/pathology , Kidney/physiopathology , Male , Middle Aged , Sodium/urine , Uric Acid/blood , Young AdultABSTRACT
PURPOSE: The aims were to assess (1) the diagnostic value of serum procalcitonin (PCT) for acute pyelonephritis (APN) in infants and children with urinary tract infections (UTIs) and (2) to compare the performance of two commonly used cutoff values. METHODS: A meta-analysis of serum PCT in the diagnosis of APN among pediatrics with lower UTIs was conducted. The process of search strategy, publications selection and data analysis was in accordance with the preferred reporting items for systematic reviews and meta-analyses guidelines. RESULTS: Eighteen high-quality studies with a total of 831 APN patients and 651 individuals with lower UTIs were analyzed. The overall performance of serum PCT ≥ 0.5 ng/mL was as follows: pooled sensitivity of 0.86 (95 % CI 0.73-0.93), pooled specificity of 0.76 (95 % CI 0.66-0.83), DOR of 18.90 (95 % CI 6.78-52.71) and AUROC of 0.86 (95 % CI 0.83-0.89), with significant heterogeneity. However, use of 1.0 ng/mL as a cutoff value produced an improved specificity of 0.91 (95 % CI 0.86-0.94), a DOR of 55.06 (95 % CI 22.57-115.48) and an AUROC of 0.94 (95 % CI 0.92-0.96), without obvious heterogeneity. CONCLUSION: In pediatrics with UTIs, the cutoff value of serum PCT, 1.0 ng/mL, has a preferable diagnostic performance compared with 0.5 ng/mL for APN. Additional prospective studies that propose an appropriate cutoff value and validate the performance of PCT for young with APN are needed in the future.
Subject(s)
Calcitonin/blood , Pyelonephritis/blood , Urinary Tract Infections/complications , Acute Disease , Biomarkers/blood , Child , Child, Preschool , Humans , Infant , Prognosis , Pyelonephritis/diagnosis , Pyelonephritis/etiology , Urinary Tract Infections/blood , Urinary Tract Infections/diagnosisABSTRACT
The diagnostic performance of M-type phospholipase A2 receptor (PLA2R) autoantibodies and PLA2R glomerular staining in discriminating between idiopathic membranous nephropathy (iMN) and secondary membranous nephropathy (sMN) has not been fully evaluated. We conducted an updated meta-analysis to investigate the accuracy and clinical value of serological anti-PLA2R test and histological PLA2R staining for differentiation iMN from sMN. A total of 19 studies involving 1160 patients were included in this meta-analysis. The overall sensitivity, specificity, diagnostic odds ratio (DOR) and area under the receiver operating characteristic curve (AUROC) of serum anti-PLA2R were 0.68 (95% CI, 0.61-074), 0.97 (95% CI, 0.85-1.00), 73.75 (95% CI, 12.56-432.96) and 0.82 (95% CI, 0.78-0.85), respectively, with substantial heterogeneity (I(2) = 86.42%). Subgroup analyses revealed the study design, publication type, study origin, assay method might account for the heterogeneity. Additionally, the overall sensitivity, specificity, DOR and AUROC of glomerular PLA2R staining were 0.78 (95% CI, 0.72-0.83), 0.91 (95% CI, 0.75-0.97), 34.70 (95% CI, 9.93-121.30) and 0.84 (95% CI, 0.81-0.87), respectively, without heterogeneity (I(2) = 0%). Serological anti-PLA2R testing has diagnostic value, but it must be interpreted in context with patient clinical characteristics and histological PLA2R staining in seronegative patients is recommended.
Subject(s)
Autoantibodies/immunology , Glomerulonephritis, Membranous/diagnosis , Glomerulonephritis, Membranous/etiology , Kidney Glomerulus/immunology , Receptors, Phospholipase A2/immunology , Autoantibodies/blood , Biopsy , Diagnosis, Differential , Glomerulonephritis, Membranous/drug therapy , Humans , Immunosuppressive Agents/therapeutic use , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Proteinuria , ROC Curve , Receptors, Phospholipase A2/metabolism , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
Methyl-CpG-binding protein 2 (MeCP2) is essential in human brain development and has been linked to several cancer types and neuro-developmental disorders. This study aims to screen the MeCP2 related differentially expressed genes and discover the therapeutic targets for osteosarcoma. CCK8 assay was used to detect the proliferation and SaOS2 and U2OS cells. Apoptosis of cells was detected by flow cytometry analysis that monitored Annexin V-APC/7-DD binding and 7-ADD uptake simultaneously. Denaturing formaldehyde agarose gel electrophoresis was employed to examine the quality of total RNA 18S and 28S units. Gene chip technique was utilized to discover the differentially expressed genes correlated with MeCP2 gene. Differential gene screening criteria were used to screen the changed genes. The gene up-regulation or down-regulation more than 1.5 times was regarded as significant differential expression genes. The CCK8 results indicated that the cell proliferation of MeCP2 silencing cells (LV-MeCP2-RNAi) was significantly decreased compared to non-silenced cells (LV-MeCP2-RNAi-CN) (P < 0.05). MeCP2 silencing could also induce significant apoptosis compared to non-silenced cells (P < 0.05); 107 expression changed genes were screened from a total of 49,395 transcripts. Among the total 107 transcripts, 34 transcripts were up-regulated and 73 transcripts were down-regulated. There were five significant differentially expressed genes, including IGFBP4, HOXC8, LMO4, MDK, and CTGF, which correlated with the MeCP2 gene. The methylation frequency of CpG in IGFBP4 gene could achieve 55%. In conclusion, the differentially expressed IGFBP4, HOXC8, LMO4, MDK, and CTGF genes may be involved in MeCP2 gene-mediated proliferation and apoptosis in osteosarcoma cells.