ABSTRACT
Accumulating evidence shows that renal fibrosis plays a key role in the development of hypertensive nephropathy (HTN). Therefore, a better understanding of the underlying mechanism of renal fibrosis regulation in HTN would be critical for designing rational strategies for therapeutic interventions. In this study, we revealed that GPR97, a novel identified adhesion G coupled receptor, plays an important role in the regulation of Wnt/ß-catenin signaling, which is the crucial driver of renal fibrosis in HTN. First, we identified that the expression of GPR97 correlated with the ß-catenin expression in renal biopsy from patients with HTN. Moreover, we found that GPR97 deficiency inhibited Wnt/ß-catenin signaling in mice with HTN, as evidenced by the reduction of ß-catenin expression and downstream target proteins, including MMP7 and Fibronectin. Mechanistically, we found that GPR97 could directly bind with Wnt1 in cultured tubular cells and TGF-ß1 treatment enhanced the binding ability of GPR97 and Wnt1. In addition, the gene silencing of GPR97 could decrease the Wnt1-induced fibrotic phenotype of tubular cells and inflammatory responses, suggesting that the binding of GPR97 and Wnt1 promoted Wnt/ß-catenin signaling. Collectively, our studies reveal that GPR97 is a regulator of Wnt/ß-catenin signaling in HTN, and targeting GPR97 may be a novel therapeutic strategy for HTN treatment.
Subject(s)
Hypertension, Renal , Nephritis , Receptors, G-Protein-Coupled , beta Catenin , Animals , Humans , Mice , beta Catenin/metabolism , Fibrosis , Wnt Signaling Pathway/physiology , Receptors, G-Protein-Coupled/deficiency , Receptors, G-Protein-Coupled/geneticsABSTRACT
Kidney fibrosis is a prominent pathological feature of hypertensive kidney diseases (HKD). Recent studies have highlighted the role of ubiquitinating/deubiquitinating protein modification in kidney pathophysiology. Ovarian tumor domain-containing protein 6 A (OTUD6A) is a deubiquitinating enzyme involved in tumor progression. However, its role in kidney pathophysiology remains elusive. We aimed to investigate the role and underlying mechanism of OTUD6A during kidney fibrosis in HKD. The results revealed higher OTUD6A expression in kidney tissues of nephropathy patients and mice with chronic angiotensin II (Ang II) administration than that from the control ones. OTUD6A was mainly located in tubular epithelial cells. Moreover, OTUD6A deficiency significantly protected mice against Ang II-induced kidney dysfunction and fibrosis. Also, knocking OTUD6A down suppressed Ang II-induced fibrosis in cultured tubular epithelial cells, whereas overexpression of OTUD6A enhanced fibrogenic responses. Mechanistically, OTUD6A bounded to signal transducer and activator of transcription 3 (STAT3) and removed K63-linked-ubiquitin chains to promote STAT3 phosphorylation at tyrosine 705 position and nuclear translocation, which then induced profibrotic gene transcription in epithelial cells. These studies identified STAT3 as a direct substrate of OTUD6A and highlighted the pivotal role of OTUD6A in Ang II-induced kidney injury, indicating OTUD6A as a potential therapeutic target for HKD.NEW & NOTEWORTHY Ovarian tumor domain-containing protein 6 A (OTUD6A) knockout mice are protected against angiotensin II-induced kidney dysfunction and fibrosis. OTUD6A promotes pathological kidney remodeling and dysfunction by deubiquitinating signal transducer and activator of transcription 3 (STAT3). OTUD6A binds to and removes K63-linked-ubiquitin chains of STAT3 to promote its phosphorylation and activation, and subsequently enhances kidney fibrosis.
Subject(s)
Hypertension, Renal , Nephritis , Ovarian Neoplasms , Humans , Mice , Animals , Female , Angiotensin II/pharmacology , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Kidney/metabolism , Hypertension, Renal/metabolism , Hypertension, Renal/pathology , Epithelial Cells/metabolism , Fibrosis , Ovarian Neoplasms/metabolism , Ubiquitins/metabolism , Mice, Inbred C57BLABSTRACT
Chronic kidney disease (CKD) is characterized by kidney inflammation and fibrosis. However, the precise mechanisms leading to kidney inflammation and fibrosis are poorly understood. Since histone deacetylase is involved in inflammation and fibrosis in other tissues, we examined the role of histone deacetylase 3 (HDAC3) in the regulation of inflammation and kidney fibrosis. HDAC3 is induced in the kidneys of animal models of CKD but mice with conditional HDAC3 deletion exhibit significantly reduced fibrosis in the kidneys compared with control mice. The expression of proinflammatory and profibrotic genes was significantly increased in the fibrotic kidneys of control mice, which was impaired in mice with HDAC3 deletion. Genetic deletion or pharmacological inhibition of HDAC3 reduced the expression of proinflammatory genes in cultured monocytes/macrophages. Mechanistically, HDAC3 deacetylates Lys122 of NF-κB p65 subunit turning on transcription. RGFP966, a selective HDAC3 inhibitor, reduced fibrosis in cells and in animal models by blocking NF-κB p65 binding to κB-containing DNA sequences. Thus, our study identified HDAC3 as a critical regulator of inflammation and fibrosis of the kidney through deacetylation of NF-κB unlocking its transcriptional activity. Hence, targeting HDAC3 could serve as a novel therapeutic strategy for CKD.
Subject(s)
Histone Deacetylases , Nephritis , Renal Insufficiency, Chronic , Animals , Mice , Fibrosis , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/genetics , Histone Deacetylases/metabolism , Inflammation/genetics , Inflammation/pathology , Kidney/pathology , Nephritis/genetics , Nephritis/pathology , NF-kappa B/metabolism , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/pathologyABSTRACT
PURPOSE: To define the clinical and histological characteristics of nephritis in patients with X-linked agammaglobulinemia (XLA) and their immunological profiles. METHODS: The clinical, immunological, and histological findings of nine patients with XLA and nephritis were retrospectively analyzed. RESULTS: Based on kidney histological findings, patients with XLA and nephritis could be divided into two groups, viz., chronic glomerulonephritis (CGN) and tubulointerstitial nephritis (TIN). The two groups showed different immunological profiles. Patients in the CGN group exhibited an atypical immunological profile of XLA, with pathogenic leaky B cells producing immunoglobulins that may play a role in forming immune complexes and causing immune-mediated glomerulonephritis. In contrast, patients in the TIN group exhibited a typical immunological profile of XLA, suggesting that antibody-independent/other BTK-dependent mechanisms, or immunoglobulin replacement therapy (IgRT)-related immune/nonimmune-mediated nephrotoxicity causes TIN. CONCLUSION: Nephritis occurring in patients with XLA could have links between their renal pathology and immunological status. Careful observation is recommended to detect kidney pathology in patients with XLA on IgRT.
Subject(s)
Agammaglobulinemia , Genetic Diseases, X-Linked , Phenotype , Humans , Agammaglobulinemia/immunology , Agammaglobulinemia/diagnosis , Agammaglobulinemia/genetics , Genetic Diseases, X-Linked/immunology , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/complications , Male , Adolescent , Child , Adult , Retrospective Studies , Child, Preschool , Young Adult , Agammaglobulinaemia Tyrosine Kinase/genetics , Nephritis, Interstitial/immunology , Nephritis, Interstitial/diagnosis , Kidney/pathology , Kidney/immunology , B-Lymphocytes/immunology , Female , Glomerulonephritis/immunology , Glomerulonephritis/diagnosis , Nephritis/immunology , Nephritis/diagnosis , Nephritis/etiologyABSTRACT
Nephritis is an inflammatory condition of the glomerulus, and the clinical gold standard for its diagnosis is a kidney biopsy. However, obtaining biopsy results can take several days, which does not meet the requirement of rapid diagnosis, especially for rapidly progressive types. To achieve an effective and noninvasive diagnosis, we propose a nephritis-specific, positive magnetic resonance imaging (MRI) contrast agent based on Gd3+ anchored walking dead macrophage Gd-RAW. Gd-RAW exhibits high selectivity for inflammatory renal parenchyma and provides comparable results to histopathology methods. The Gd-RAW-based MRI contrast agent reduces the diagnostic time of nephritis from 14 days of biopsy to 1 h. Furthermore, in a unilateral nephritis model constructed by increasing the glycerol concentration, the T1WI of renal parenchyma exhibits an increased signal-to-noise ratio, which is crucial for evaluating nephritic severity. This work promotes rapid diagnosis of nephritis and potentially provides sufficient evidence for clinicians to offer timely treatment to patients. The methodology of paramagnetic ion-anchored macrophage corpse also opens up new prospects for designing more specific and biosafe MRI contrast agents.
Subject(s)
Contrast Media , Nephritis , Humans , Kidney/diagnostic imaging , Nephritis/diagnostic imaging , Kidney Glomerulus , Magnetic Resonance Imaging/methodsABSTRACT
Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance.
Subject(s)
Heart Diseases , Hypertension, Renal , Nephritis , Humans , Cytochrome P-450 CYP11B2/genetics , Cytochrome P-450 CYP11B2/metabolism , Aldosterone/pharmacology , Hypothalamo-Hypophyseal System/metabolism , Pituitary-Adrenal System/metabolism , Hypertension, Renal/drug therapy , Renin-Angiotensin System , Mineralocorticoid Receptor Antagonists/therapeutic use , Mineralocorticoid Receptor Antagonists/pharmacology , Heart Diseases/drug therapyABSTRACT
PURPOSE OF REVIEW: To present findings indicating the value of kidney biopsy in assessing prognosis and guiding clinical approach to patients with IgA vasculitis nephritis (IgAVN), including a recent international study examining the value of the Oxford (MEST-C) classification. RECENT FINDINGS: Historically, kidney biopsies with IgAVN are scored using the International Society for Kidney Diseases in Children (ISKDC) classification. However, this classification has limited prognostic value, and most biopsies fall into just two of the six ISKDC grades. There are few studies examining the clinical value of the Oxford classification, which is well documented to be predictive of kidney outcomes in IgA nephropathy, in IgAVN. However, a recent study of 361 biopsied patients with IgAVN showed that endocapillary hypercellularity (Oxford E1) predicted a subclass of patients showing initial improvement in kidney function with immunosuppressive treatment, followed by a later decline. SUMMARY: Kidney outcome in patients with biopsied IgAVN treated with immunosuppression is determined by clinical factors and endocapillary hypercellularity. The latter is not part of the ISKDC classification and supports including MEST-C scores in biopsy reports of IgAVN. Even patients showing a good initial response to immunosuppression require long-term follow-up due to risk of subsequent kidney function decline.
Subject(s)
Glomerulonephritis, IGA , IgA Vasculitis , Nephritis , Child , Humans , IgA Vasculitis/diagnosis , IgA Vasculitis/pathology , Kidney/pathology , Glomerulonephritis, IGA/drug therapy , BiopsyABSTRACT
INTRODUCTION: Hypertensive nephrosclerosis (HN) ranks as one of the most frequent causes of chronic kidney disease (CKD), but its very existence has repeatedly been called into question, especially in young adults. Its diagnostic framework is established chiefly on non-specific clinical criteria, and its defining histopathological set of features is in fact shared by numerous other conditions. Genetic testing based on exome sequencing (ES) has emerged as a comprehensive tool to detect Mendelian diseases in timely fashion in nephrology, with a significant number of re-established diagnoses. The aim of this study was to investigate the diagnostic yield of ES in patients with a clinical diagnosis of hypertensive nephropathy. METHOD: Since September 2018, ES has been readily available as part of the routine diagnostic work-up in our institution. The indication of ES includes hypertensive nephropathy of early onset (i.e., <45 years old). We retrospectively collected the ES data performed in the context of hypertensive nephropathy in our institution between September 2018 and February 2021. RESULTS: A total of 128 patients were sequenced in the context of hypertensive nephropathy with early onset. The chief indications of ES were an early onset of CKD (47%), family history of kidney disease (8%), or both (18%). We detected diagnostic variants in 19 of the 128 patients (15%), encompassing a total of 13 different monogenic disorders. The diagnostic yield of ES was lower in patients of African ancestry (diagnostic yield of 7 vs. 30% in non-African ancestry patients, p < 0.001). CONCLUSIONS: The high diagnostic yield of ES (15%) in a population of patients thought to have HN casts further doubts on the validity of the existing diagnosis criteria, including histological criteria, supposed to characterize the condition. This was especially true in patients with no African ancestry, where ES positivity reached 30%.
Subject(s)
Exome Sequencing , Hypertension, Renal , Humans , Male , Female , Adult , Middle Aged , Retrospective Studies , Hypertension, Renal/genetics , Hypertension, Renal/diagnosis , Age of Onset , Nephritis/genetics , Nephritis/diagnosis , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/diagnosis , Nephrosclerosis/genetics , Nephrosclerosis/diagnosisABSTRACT
Background: Renal impairments commonly occur as a complication of autoimmune connective tissue diseases (CTDs). Therefore, early nephritis prediction is vital for patient outcomes. Growth Arrest-Specific Protein 6 (GAS6) was found to be upregulated in many types of inflammatory renal disease, including diabetic nephropathy.Aim: To evaluate GAS6 as a predictor of renal impairment in adults with systemic sclerosis (SSc) and children with systemic lupus Erythematosus (SLE).Methods: The study included 60 patients with SSc and 40 children with SLE. The serum level of GAS6 was measured using the ELISA technique. In adults with SSc, total proteins in 24-h urine concentration of >300 mg/24 h indicated renal inflammation, while in children with SLE, nephritis was diagnosed by abnormal renal pathology.Results: In SSc patients, GAS6 significantly increased in patients with proteinuria. GAS6 is an independent predictor of nephritis with an odds ratio (OR) of 1.06 and a 95% confidence interval (CI) of 1.0-1.1. at cutoff 12.2 ng/mL GAS6 predicted proteinuria with sensitivity 86.7% (95% CI: 59.5% to 98.3%), specificity 57.8% (95% CI: 42.1% to 72.3%), positive predictive value 40.6% (95% CI: 31.5% to 50.4%), negative predictive value 92.9% (95% CI: 77.7% to 97.73%), and accuracy 65.0% (95% CI: 51.6% to 76.9%). In SLE patients, Serum GAS6 did not differ significantly between children with and without lupus nephritis.Conclusion: GAS6 is an independent predictor of nephritis in patients with SSc. However, there is no association between GAS6 and nephritis in juvenile patients with SLE.
Subject(s)
Biomarkers , Intercellular Signaling Peptides and Proteins , Lupus Erythematosus, Systemic , Lupus Nephritis , Scleroderma, Systemic , Adult , Female , Humans , Male , Middle Aged , Young Adult , Biomarkers/blood , Enzyme-Linked Immunosorbent Assay , Intercellular Signaling Peptides and Proteins/blood , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/blood , Lupus Nephritis/blood , Lupus Nephritis/urine , Lupus Nephritis/diagnosis , Nephritis/etiology , Nephritis/blood , Nephritis/urine , Nephritis/diagnosis , Predictive Value of Tests , Proteinuria/etiology , Scleroderma, Systemic/complications , Scleroderma, Systemic/blood , AgedABSTRACT
BACKGROUND: This study investigated whether nature of primary renal disease affects clinical outcomes after renal transplantation at a single center in the United Kingdom. METHODS: This was a retrospective cohort study of 961 renal transplant recipients followed up at a large renal center from 2000 to 2020. Separation of diseases responsible for end-stage kidney disease included glomerulonephritis, diabetic kidney disease, hypertensive nephropathy, autosomal dominant polycystic kidney disease, unknown cause, other causes and chronic pyelonephritis. Outcome data included graft loss, cardiovascular events, malignancy, post-transplant diabetes mellitus and death, analyzed according to primary disease type. RESULTS: The mean age at transplantation was 47.3 years. During a mean follow-up of 7.6 years, 18% of the overall cohort died corresponding to an annualised mortality rate of 2.3%. Death with a functioning graft occurred at a rate of 2.1% per annum, with the highest incidence observed in in patients with diabetic kidney disease (4.1%/year). Post-transplant cardiovascular events occurred in 21% of recipients (2.8% per year), again highest in recipients with diabetic kidney disease (5.1%/year) and hypertensive nephropathy (4.5%/year). Post-transplant diabetes mellitus manifested in 19% of the cohort at an annualized rate of2.1% while cancer incidence stood at 9% with an annualized rate of 1.1% . Graft loss occurred in 6.8% of recipients at the rate of1.2% per year with chronic allograft injury, acute rejection and recurrent glomerulonephritis being the predominant causative factors. Median + IQR dialysis-free survival of the whole cohort was 16.2 (9.9 - > 20) years, being shortest for diabetic kidney disease (11.0 years) and greatest for autosomal dominant polycystic kidney disease (18.2 years) .The collective mean decline in eGFR over time was -1.14ml/min/year. Recipients with Pre-transplant diabetic kidney disease exhibited the fastest rate of decline(-2.1ml/min/year) a statistically significant difference in comparison to the other native kidney diseases with Autosomal dominant polycystic kidney disease exhibiting the lowest rate of decline(-0.05ml/min/year) CONCLUSION: Primary renal disease can influence the outcome after renal transplantation, with patients with prior diabetic kidney disease having the poorest outcome in terms of dialysis-free survival and loss of transplant function. Autosomal polycystic kidney disease, other cause and unknown cause had the best outcomes compared to other primary renal disease groups.
Subject(s)
Diabetic Nephropathies , Glomerulonephritis , Hypertension, Renal , Kidney Transplantation , Nephritis , Polycystic Kidney, Autosomal Dominant , Humans , Middle Aged , Kidney Transplantation/adverse effects , Retrospective StudiesABSTRACT
Hypertensive renal disease (HRD) contributes to the progression of kidney dysfunction and ultimately leads to end-stage renal disease. Understanding the mechanisms underlying HRD is critical for the development of therapeutic strategies. Deubiquitinating enzymes (DUBs) have been recently highlighted in renal pathophysiology. In this study, we investigated the role of a DUB, OTU Domain-Containing Protein 1 (OTUD1), in HRD models. HRD was induced in wild-type or Otud1 knockout mice by chronic infusion of angiotensin II (Ang II, 1 µg/kg per min) through a micro-osmotic pump for 4 weeks. We found that OTUD1 expression levels were significantly elevated in the kidney tissues of Ang II-treated mice. Otud1 knockout significantly ameliorated Ang II-induced HRD, whereas OTUD1 overexpression exacerbated Ang II-induced kidney damage and fibrosis. Similar results were observed in TCMK-1 cells but not in SV40 MES-13 cells following Ang II (1 µM) treatment. In Ang II-challenged TCMK-1 cells, we demonstrated that OTUD1 bound to CDK9 and induced CDK9 deubiquitination: OTUD1 catalyzed K63 deubiquitination on CDK9 with its Cys320 playing a critical role, promoting CDK9 phosphorylation and activation to induce inflammatory responses and fibrosis in kidney epithelial cells. Administration of a CDK9 inhibitor NVP-2 significantly ameliorated Ang II-induced HRD in mice. This study demonstrates that OTUD1 mediates HRD by targeting CDK9 in kidney epithelial cells, suggesting OTUD1 is a potential target in treating this disease.
Subject(s)
Hypertension, Renal , Kidney , Nephritis , Ubiquitin-Specific Proteases , Animals , Mice , Angiotensin II/metabolism , Epithelial Cells/metabolism , Fibrosis , Hypertension, Renal/enzymology , Hypertension, Renal/pathology , Kidney/pathology , Mice, Inbred C57BL , Mice, Knockout , Nephritis/enzymology , Nephritis/pathology , Ubiquitin-Specific Proteases/metabolism , Disease Models, AnimalABSTRACT
Henoch-Schönlein purpura nephritis (HSPN) is the most severe manifestation of Henoch-Schönlein purpura (HSP). This study aimed to determine the role of urine metabolomics in predicting HSPN and explore the potential mechanisms of HSP. A liquid chromatography-tandem mass spectrometry-based untargeted metabolomics analysis was performed to investigate the urinary metabolic profiles of 90 participants, comprising 30 healthy children (group CON) and 60 patients with HSP, including 30 HSP patients without renal involvement (group H) and 30 HSPN patients (group HSPN). The differentially expressed metabolites (DEMs) were identified using orthogonal partial least squares discriminant analysis (OPLS-DA), and subsequent bioinformatics analysis was conducted to elucidate the perturbed metabolic pathways. A total of 43 DEMs between H and HSPN groups were analyzed by the Kyoto Encyclopedia of Gene and Genome (KEGG) database, and the result indicates that glycine, serine and threonine metabolism, and cysteine and methionine metabolism were significantly disturbed. A composite model incorporating propionylcarnitine and indophenol sulfate was developed to assess the risk of renal involvement in pediatric patients with HSP. Conclusion: This study reveals the metabolic alterations in healthy children, HSPN patients, and HSP patients without renal involvement. Furthermore, propionylcarnitine and indophenol sulfate may be potential predictive biomarkers of the occurrence of HSPN. What is Known: ⢠HSP is the predominant type of vasculitis observed in children. The long-term prognosis of HSP is contingent upon the extent of renal impairment. In severe nephritis, a delay in appropriate treatment may lead to fibrosis progression and subsequent development of chronic kidney disease (CKD), even leading to renal failure. ⢠The application of metabolomics in investigating diverse renal disorders has been documented. Urine is a robust and sensitive medium for metabolomics detection. What is New: ⢠The metabolic profiles were identified in urine samples of healthy children and those with HSP at the early stage of the disease. Different metabolites were identified between HSP patients without nephritis and those who developed HSPN. ⢠These different metabolites may affect oxidative stress in the progression of HSPN.
Subject(s)
Biomarkers , IgA Vasculitis , Metabolomics , Nephritis , Humans , IgA Vasculitis/urine , IgA Vasculitis/complications , IgA Vasculitis/diagnosis , Male , Female , Child , Nephritis/urine , Nephritis/etiology , Pilot Projects , Biomarkers/urine , Metabolomics/methods , Case-Control Studies , Child, Preschool , Chromatography, Liquid , Tandem Mass Spectrometry , AdolescentABSTRACT
Hypertension affects a large number of individuals globally and is a common cause of nephropathy, stroke, ischaemic heart disease and other vascular diseases. While many anti-hypertensive medications are used safely and effectively in clinic practice, controlling hypertensive complications solely by reducing blood pressure (BP) can be challenging. α-Mangostin, a xanthone molecule extracted from the pericarp of Garcinia mangostana L., has shown various beneficial effects such as anti-tumor, anti-hyperuricemia, and anti-inflammatory properties. However, the effects of α-Mangostin on hypertension remain unknown. In this study, we observed that α-Mangostin significantly decreased systolic and diastolic blood pressure in spontaneously hypertensive rats (SHR), possibly through the down-regulation of angiotensin II (Ang II). We also identified early markers of hypertensive nephropathy, including urinary N-acetyl-ß-D-glucosaminidase (NAG) and ß2-microglobulin (ß2-MG), which were reduced by α-Mangostin treatment. Mechanistic studies suggested that α-Mangostin may inhibit renal tubular epithelial-to-mesenchymal transformation (EMT) by down-regulating the TGF-ß signaling pathway, thus potentially offering a new therapeutic approach for hypertension and hypertensive nephropathy.
Subject(s)
Angiotensin II , Blood Pressure , Epithelial-Mesenchymal Transition , Hypertension , Xanthones , Animals , Humans , Male , Rats , Angiotensin II/metabolism , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Blood Pressure/drug effects , Cell Line , Epithelial-Mesenchymal Transition/drug effects , Fibrosis/drug therapy , Garcinia mangostana/chemistry , Hypertension/drug therapy , Hypertension/pathology , Hypertension, Renal/drug therapy , Hypertension, Renal/pathology , Nephritis , Rats, Inbred SHR , Signal Transduction/drug effects , Xanthones/pharmacology , Xanthones/therapeutic useABSTRACT
BACKGROUND: The guidelines in Japan for the treatment of rapidly progressive glomerulonephritis (RPGN) have been revised; the latest update was released in 2020. We investigated the actual usage of the new guidelines in Japan. METHODS: We distributed a survey electronically to board-certified nephrologists throughout Japan from December 15, 2021 to January 31, 2022. The survey focused on anti-neutrophil cytoplasmic antibody (ANCA)-associated RPGN and anti-glomerular basement membrane (GBM)-antibody RPGN, plus the treatment strategies and infection-prevention measures used. RESULTS: The survey was completed by 155 certified nephrologists from medical facilities across Japan. Their responses regarding treatment procedures revealed that ANCA-associated RPGN was treated with immunosuppressants and/or biologics by 58.1% of the survey respondents, and with plasma exchange (PE) in combination with corticosteroids by 21.3%. Regarding anti-GBM-antibody RPGN, 78.1% of the respondents used corticosteroids in combination with PE (63.2%), cyclophosphamide (CY) (23.9%), or rituximab (RTX) (8.4%), suggesting a discrepancy between clinical practice and the actual use of the guidelines. Trimethoprim-sulfamethoxazole was prescribed as prophylaxis by 94.8% of the respondents, reflecting the widespread recognition of the need to prevent infectious disease in patients with RPGN. CONCLUSIONS: The survey responses revealed how Japan's new RPGN guidelines are used in actual clinical practice. Our findings will contribute to the guidelines' dissemination and implementation.
Subject(s)
Glomerulonephritis , Nephritis , Humans , Adrenal Cortex Hormones , Antibodies, Antineutrophil Cytoplasmic , Glomerulonephritis/drug therapy , Japan , Nephrologists , Surveys and Questionnaires , Practice Guidelines as TopicABSTRACT
BACKGROUND: The objective of this study is to investigate the clinical and pathological differences between patients with IgA nephropathy (IgAN) and IgA vasculitis associated nephritis (IgAVN). METHODS: A total of 253 patients with IgAN and 71 patients with IgAVN were retrospectively included in the study, and clinical and laboratory data were collected and analysed. RESULTS: Compared with IgAVN group, months from onset to kidney biopsy were significantly prolonged in IgAN patients because of the lack of obvious symptoms such as rash, abdominal symptoms, and joint pain (13.5 ± 26.6 vs. 10.2 ± 31.6 months, P = 0.007), and the levels of serum creatinine (92.3 ± 94.7 vs. 68.9 ± 69.2 µmol/L, P = 0.015) was higher and eGFR (99.1 ± 35.2 vs. 123.4 ± 41.8 mL/min/1.73m2, P < 0.001) was lower in IgAN group. The pathological results revealed that patients with IgAN have a greater degree of chronic kidney injury compared to patients with IgAVN. In addition, the levels of plasma D-Dimers (1415.92 ± 1774.69 vs. 496.78 ± 711.91 ng/mL, P < 0.001) and fibrinogen degradation products (FDP) (3.92 ± 4.73 vs. 1.63 ± 2.46 µg/mL, P = 0.001) were significantly higher in IgAVN patients than in IgAN patients. The deposition of fibrinogen in the renal tissues was more severe and the cumulative partial remission rate was higher in patients with IgAVN as compared to those with IgAN (P = 0.001). CONCLUSIONS: In comparison, IgAN patients had poorer renal function, whereas IgAVN patients had more severe coagulation abnormalities. These findings provide a basis for the differentiation of the two diseases at an early stage.
Subject(s)
Glomerulonephritis, IGA , IgA Vasculitis , Nephritis , Humans , Glomerulonephritis, IGA/diagnosis , IgA Vasculitis/diagnosis , Retrospective Studies , Kidney/pathology , Nephritis/etiology , FibrinogenABSTRACT
BACKGROUND: Globally, there are regional and time-based variations in the prevalence, etiology, and prognosis of rapidly progressive glomerulonephritis (RPGN). Prognosis of RPGN is poor, with a higher risk of death and end stage renal disease (ESRD) even with immunosuppressive medications. In the Middle East and North Africa, the studies on this disease are very limited. Therefore, we determined the predictors of outcome of RPGN. METHODS: We retrospectively assessed 101 adult patients over age of 18, diagnosed with RPGN based on renal biopsy illustrating crescents in ≥ 50% of the glomeruli. Patients who had crescents in their renal biopsies that were < 50% and those who refused to consent to a renal biopsy were excluded. We categorized the patients into 3 groups based on immunohistochemistry; type I, type II and type III. Then, depending on renal loss, we divided them into ESRD and non-ESRD groups. The clinical history and physical examination were retrieved. Additionally, 24-hour urine protein, urine analysis, renal function tests, serum albumin, complete blood count, antinuclear antibodies, anti-double stranded DNA antibodies, ANCA antibodies and serum complement levels were checked. Each patient underwent a kidney biopsy for immunohistochemistry and light microscopy. The percentage of crescentic glomeruli, number of sclerosed glomeruli, tertiary lymphoid organ (TLO), neutrophil infiltration, endocapillary or mesangial hypercellularity, interstitial fibrosis with tubular atrophy (IFTA) were analyzed. Primary outcomes (remission, ESRD and mortality) and secondary outcomes were assessed. RESULTS: Type II was the most frequent cause of RPGN (47.5%), followed by type III (32.7%) and type I (19.8%). 32 patients (31.7%) died during follow up, whereas 60 patients (59.4%) developed ESRD. In 41 patients (40.6%), remission occurred. Oliguria, serum creatinine, and need for HD at presentation were significantly increased in ESRD group compared to non-ESRD group (P < 0.001 for each). Mesangial proliferation, IFTA, TLO formation, sclerotic glomeruli and fibrous crescents were also significantly increased in ESRD group in comparison to non-ESRD group (P < 0.001 for each). Glomerulosclerosis (P = 0.036), and IFTA (P = 0.008) were predictors of ESRD. Infections (P = 0.02), respiratory failure (P < 0.001), and heart failure (P = 0.004) were mortality risk factors. CONCLUSION: Type II RPGN was the most common. Infection was the most frequent secondary outcome. Oliguria, glomerulosclerosis, the requirement for hemodialysis at presentation, IFTA and TLO formation were predictors of ESRD. Respiratory failure, heart failure and infections were significant predictors of mortality.
Subject(s)
Glomerulonephritis , Heart Failure , Kidney Failure, Chronic , Nephritis , Respiratory Insufficiency , Adult , Humans , Retrospective Studies , Glomerulonephritis/diagnosis , Oliguria , Disease Progression , Kidney/pathology , Nephritis/complications , Kidney Failure, Chronic/diagnosis , Heart Failure/complications , Respiratory Insufficiency/complicationsABSTRACT
BACKGROUND: Sepsis is a life-threatening, systemic inflammatory disease that can lead to a variety of conditions, including septic acute kidney injury (AKI). Recently, multiple circular Rnas (circRNAs) have been implicated in the development of this disease. METHODS: In this study, we aimed to elucidate the role of circ-Gatad1 in sepsis induced AKI and its potential mechanism of action. High-throughput sequencing was used to investigate abnormal expression of circRNA in AKI and healthy volunteer. Bioinformatics analysis and luciferase reporting analysis were used to clarify the interacted relationship among circRNA, miRNA and mRNA. HK2 cells were treated with lipopolysaccharide (LPS) to establish septic AKI cell model. HK2 cells were employ to analysis the ROS, inflammatory cytokines expression, proliferation and apoptosis under LPS condition. RESULTS: The result show that the expression of circ-Gatad1 was increased in septic acute kidney patients. Downregulation circ-Gatad1 suppressed LPS-treated induced HK2 cells injury including apoptosis, proliferation ability, ROS and inflammatory cytokines level. Bioinformatics and luciferase report analysis confirmed that both miR-22-3p and TRPM7 were downstream targets of circ-Gatad1. Overexpression of TRPM7 or downregulation of miR-22-3p reversed the protective effect of si-circ-Gatad1 to HK2 after exposure to LPS (5 µg/ml) microenvironment. CONCLUSION: In conclusion, knockdown of circ-Gatad1 alleviates LPS induced HK2 cell injury via targeting miR-22-3p/TRPM7 axis in septic acute kidney.
Subject(s)
Acute Kidney Injury , MicroRNAs , Nephritis , Sepsis , TRPM Cation Channels , Humans , Acute Kidney Injury/genetics , Cytokines , Kidney , Lipopolysaccharides/toxicity , Luciferases , MicroRNAs/genetics , Protein Serine-Threonine Kinases , Reactive Oxygen Species , RNA, Circular/genetics , Sepsis/geneticsABSTRACT
BACKGROUND: The obesity epidemic is associated with the emergence of new kidney diseases including obesity-related glomerulopathy (ORG) and metabolic syndrome-associated disorders. However, the effects of obesity on prevalence and outcome of biopsy-proven kidney disease are not well known. METHODS: We analyzed 14,492 kidney biopsies in 18 hospitals from 1979 to 2018 in Korea. Obesity was defined as a body mass index value of ≥ 30 kg/m². RESULTS: The most common disease was IgA nephropathy (IgAN) in both obese and non-obese participants (33.7% vs. 38.9%). Obesity was associated with a higher risk of focal segmental glomerulosclerosis (FSGS) and hypertensive nephropathy (HT-N) (odds ratio [OR], 1.72, 95% confidence interval [CI], 1.37-2.17; OR, 1.96, 95% CI, 1.21-3.19) and a lower risk of IgAN (OR, 0.74, 95% CI, 0.62-0.88). During the median follow up of 93.1 ± 88.7 months, obesity increased the risk of end-stage kidney disease (ESKD) in patients with IgAN (relative risk [RR], 1.49, 95% CI, 1.01-2.20) and lupus nephritis (LN) (RR, 3.43, 95% CI, 1.36-8.67). Of 947 obese individuals, ORG was detected in 298 (31.5%), and 230 participants had other kidney diseases, most commonly, IgAN (40.9%) followed by diabetic nephropathy (15.2%). Participants with ORG, when combined with other renal diseases, showed higher risks for developing ESKD compared to those with ORG alone (RR, 2.48, 95% CI, 1.09-5.64). CONCLUSION: Obesity is associated with an increased risk of FSGS and HT-N, and also increase the ESKD risk in IgAN and LN patients. ORG in obese participants may have favorable renal outcomes if it occurs alone without any other renal disease.
Subject(s)
Glomerulonephritis, IGA , Glomerulosclerosis, Focal Segmental , Hypertension, Renal , Nephritis , Humans , Glomerulosclerosis, Focal Segmental/complications , Glomerulosclerosis, Focal Segmental/epidemiology , Kidney , Obesity/complications , Biopsy , Cohort Studies , Glomerulonephritis, IGA/complications , Glomerulonephritis, IGA/diagnosisABSTRACT
Henoch-Schonlein purpura nephritis (HSPN) is a systemic vascular inflammatory disease. Huanglian Decoction (HLD) ameliorates renal injury in nephritis; however, the mechanism of action of HLD on HSPN has not been investigated. This study aimed to investigate the protective mechanism of HLD treatment in HSPN. The effects of HLD on HSPN biochemical indices, kidney injury and NF-κB/NLRP3 signaling pathway were analyzed by biochemical analysis, ELISA, HE and PAS staining, immunohistochemistry, immunofluorescence, and Western Blot. In addition, the effects of HLD on HSPN cells were analyzed. We found that HLD treatment significantly reduced renal tissue damage, decreased the levels of IL-17, IL-18, TNF-α, and IL-1ß, and increased the levels of TP and ALB in HSPN mice. It also inhibited the deposition of IgA, IgG, and C3 in kidney tissues and significantly decreased the expression of IκBα, p-IκBα, NLRP3, caspase-1, and IL-1ß in kidney tissues and cells. In addition, PMA treatment inhibited the above-mentioned effects of HLD. These results suggested that HLD attenuates renal injury, IgA deposition, and inflammation in HSPN mice and its mechanism of action may be related to the inhibition of the NF-κB/NLRP3 pathway.
Subject(s)
Drugs, Chinese Herbal , IgA Vasculitis , Nephritis , Animals , Mice , IgA Vasculitis/drug therapy , NF-kappa B , NF-KappaB Inhibitor alpha , NLR Family, Pyrin Domain-Containing 3 Protein , Kidney , Nephritis/drug therapy , Immunoglobulin A , Signal TransductionABSTRACT
Hypertensive nephropathy continues to be a major cause of end-stage renal disease and poses a significant global health burden. Despite the staggering development of research in hypertensive nephropathy, scientists and clinicians can only seek out useful information through articles and reviews, it remains a hurdle for them to quickly track the trend in this field. This study uses the bibliometric method to identify the evolutionary development and recent hotspots of hypertensive nephropathy. The Web of Science Core Collection database was used to extract publications on hypertensive nephropathy from January 2000 to November 2023. CiteSpace was used to capture the patterns and trends from multi-perspectives, including countries/regions, institutions, keywords, and references. In total, 557 publications on hypertensive nephropathy were eligible for inclusion. China (n = 208, 37.34%) was the most influential contributor among all the countries. Veterans Health Administration (n = 19, 3.41%) was found to be the most productive institution. Keyword bursting till now are renal fibrosis, outcomes, and mechanisms which are predicted to be the potential frontiers and hotspots in the future. The top seven references were listed, and their burst strength was shown. A comprehensive overview of the current status and research frontiers of hypertensive nephropathy has been provided through the bibliometric perspective. Recent advancements and challenges in hypertensive nephropathy have been discussed. These findings can offer informative instructions for researchers and scholars.