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Children (Basel, Switzerland) Jun 2024A ~3-kb deletion-type DNA copy number variation (CNV, esv3587290) located at intron 7 of the gene (1p13.1, MIM*610132) has been proposed as a genetic factor in lupus...
Does the esv3587290 Copy Number Variation in the Gene Differ as a Genetic Factor for Developing Nephritis in Mexican Childhood-Onset Systemic Lupus Erythematosus Patients?
A ~3-kb deletion-type DNA copy number variation (CNV, esv3587290) located at intron 7 of the gene (1p13.1, MIM*610132) has been proposed as a genetic factor in lupus nephritis (LN) development in adult systemic lupus erythematosus (SLE) patients across European-descent populations, but its replication in other ethnicities has been inconsistent and its association with LN in childhood-onset SLE (cSLE) remains unknown. Here, we performed an exploratory association study in a sample of 66 unrelated cSLE Mexican patients (11 males, 55 females; ages 7.8 to 18.6 years). Two stratified groups were compared: cSLE patients with (N = 39) or without (N = 27) LN, as diagnosed by renal biopsy (N = 17), proteinuria (N = 33), urinary protein-creatinine ratio > 0.2 (N = 34), and erythrocyturia and/or granular casts in urinary sediment (N = 16). For esv3587290 CNV genotyping, we performed an end-point PCR assay with breakpoint confirmation using Sanger sequencing. We also determined the allelic frequencies of the esv3587290 CNV in 181 deidentified ethnically matched individuals (reference group). The obtained genotypes were tested for Hardy-Weinberg equilibrium using the χ test. Associations between LN and esv3587290 CNV were tested by calculating the odds ratio (OR) and using Pearson's χ tests, with a 95% confidence interval and ≤ 0.05. The esv3587290 CNV allele (OR 0.108, 95% CI 0.034-0.33, = 0.0003) and the heterozygous genotype (OR 0.04, 95% CI 0.119-0.9811, = 0.002) showed a significant protective effect against LN development. Finally, we characterized the precise breakpoint of the esv3587290 CNV to be NG_016548.1(NM_138959.3):c.1314+1339_1315-897del in our population. This report supports the notion that a broad genetic heterogeneity underlies the susceptibility for developing LN.
PubMed: 38929291
DOI: 10.3390/children11060712 -
International Journal of Molecular... Jun 2024Oil-Gan is the fruit of the genus L. The fruits have excellent effects on health care and development values. There are many methods for the management of diabetic...
Oil-Gan is the fruit of the genus L. The fruits have excellent effects on health care and development values. There are many methods for the management of diabetic nephropathy (DN). However, there is a lack of effective drugs for treating DN throughout the disease course. The primary aim of this study was to examine the protective effects (including analyses of urine and blood, and inflammatory cytokine levels) and mechanisms of the ethyl acetate extract of (EPE) on db/db mice, an animal model of diabetic nephropathy; the secondary aim was to examine the expression levels of p- protein kinase Cα (PKCα)/t-PKCα in the kidney and its downregulation of vascular endothelial growth factor (VEGF) and fibrosis gene transforming growth factor-β1 (TGF-β1) by Western blot analyses. Eight db/m mice were used as the control group. Forty db/db mice were randomly divided into five groups. Treatments included a vehicle, EPE1, EPE2, EPE3 (at doses of 100, 200, or 400 mg/kg EPE), or the comparative drug aminoguanidine for 8 weeks. After 8 weeks of treatment, the administration of EPE to db/db mice effectively controlled hyperglycemia and hyperinsulinemia by markedly lowering blood glucose, insulin, and glycosylated HbA1c levels. The administration of EPE to db/db mice decreased the levels of BUN and creatinine both in blood and urine and reduced urinary albumin excretion and the albumin creatine ratio (UACR) in urine. Moreover, EPE treatment decreased the blood levels of inflammatory cytokines, including kidney injury molecule-1 (KIM-1), C-reactive protein (CRP), and NLR family pyrin domain containing 3 (NLRP3). Our findings showed that EPE not only had antihyperglycemic effects but also improved renal function in db/db mice. A histological examination of the kidney by immunohistochemistry indicated that EPE can improve kidney function by ameliorating glomerular morphological damage following glomerular injury; alleviating proteinuria by upregulating the expression of nephrin, a biomarker of early glomerular damage; and inhibiting glomerular expansion and tubular fibrosis. Moreover, the administration of EPE to db/db mice increased the expression levels of p- PKCα/t-PKCα but decreased the expression levels of VEGF and renal fibrosis biomarkers (TGF-β1, collagen IV, p-Smad2, p-Smad3, and Smad4), as shown by Western blot analyses. These results implied that EPE as a supplement has a protective effect against renal dysfunction through the amelioration of insulin resistance as well as the suppression of nephritis and fibrosis in a DN model.
Topics: Animals; Diabetic Nephropathies; Plant Extracts; Mice; Phyllanthus emblica; Male; Disease Models, Animal; Diabetes Mellitus, Experimental; Acetates; Vascular Endothelial Growth Factor A; Kidney; Transforming Growth Factor beta1; Protein Kinase C-alpha; Blood Glucose
PubMed: 38928391
DOI: 10.3390/ijms25126686 -
Biomedicines May 2024Alport syndrome is a hereditary disease caused by mutations in the genes encoding the alpha 3, alpha 4, and alpha 5 chains of type IV collagen. It is characterized by... (Review)
Review
Alport syndrome is a hereditary disease caused by mutations in the genes encoding the alpha 3, alpha 4, and alpha 5 chains of type IV collagen. It is characterized by hematuria, proteinuria, progressive renal dysfunction, hearing loss, and ocular abnormalities. The main network of type IV collagen in the glomerular basement membrane is composed of α3α4α5 heterotrimer. Mutations in these genes can lead to the replacement of this network by an immature network composed of the α1α1α2 heterotrimer. Unfortunately, this immature network is unable to provide normal physical support, resulting in hematuria, proteinuria, and progressive renal dysfunction. Current treatment options for Alport syndrome include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which aim to alleviate glomerular filtration pressure, reduce renal injury, and delay the progression of renal dysfunction. However, the effectiveness of these treatments is limited, highlighting the need for novel therapeutic strategies and medications to improve patient outcomes. Gene therapy, which involves the use of genetic material to prevent or treat diseases, holds promise for the treatment of Alport syndrome. This approach may involve the insertion or deletion of whole genes or gene fragments to restore or disrupt gene function or the editing of endogenous genes to correct genetic mutations and restore functional protein synthesis. Recombinant adeno-associated virus (rAAV) vectors have shown significant progress in kidney gene therapy, with several gene therapy drugs based on these vectors reaching clinical application. Despite the challenges posed by the structural characteristics of the kidney, the development of kidney gene therapy using rAAV vectors is making continuous progress. This article provides a review of the current achievements in gene therapy for Alport syndrome and discusses future research directions in this field.
PubMed: 38927366
DOI: 10.3390/biomedicines12061159 -
Biomedicines May 2024Glomerular diseases (GDs), significant causes of end-stage kidney disease, are better understood through epidemiological studies based on kidney biopsies (KBs), which...
Glomerular diseases (GDs), significant causes of end-stage kidney disease, are better understood through epidemiological studies based on kidney biopsies (KBs), which provide important insights into their prevalence and characteristics. This study aims to analyze the clinicopathological features of GDs diagnosed from 2008 to 2017 at Romania's largest reference center. In this decade-long study, 1254 adult patients diagnosed with GDs were included. The local previously validated renal histopathological prognostic score was calculated for each KB using four histopathologic lesions: global glomerulosclerosis, tubular atrophy, interstitial fibrosis and fibrocellular/fibrous crescents. The mean patient age was 50 years, with a male predominance (57%). The primary referral reasons were nephrotic syndrome (46%), nephritic syndrome (37%), chronic kidney disease (12%), asymptomatic urinary abnormalities (4%), and acute kidney injury (1%). Immunoglobulin A nephropathy (IgAN) was the most frequently diagnosed GD (20%), aligning with frequencies reported in European registries. Diabetic glomerular nephropathy was the most common secondary GD (10%). It also presented the highest median renal histopathological prognostic score (2), indicating a poorer prognosis. Lower eGFR and higher proteinuria were independently associated with higher scores. This decade-long study highlights IgAN as the most frequent GD diagnosed by KB. Diabetic glomerular nephropathy was identified as the most common secondary GD. The renal histopathological prognostic score, notably high in diabetic glomerular nephropathy patients, was correlated with lower eGFR and higher proteinuria, underlining its clinical relevance.
PubMed: 38927350
DOI: 10.3390/biomedicines12061143 -
Veterinary Sciences May 2024In the present case report, we describe the clinical course and postmortem findings of a 12-year-old Labrador retriever dog with a third-degree atrio-ventricular block...
In the present case report, we describe the clinical course and postmortem findings of a 12-year-old Labrador retriever dog with a third-degree atrio-ventricular block that developed a chronic cough, and later dyspnea and weakness as a result of massive pulmonary thromboembolism 3 years after implantation of a transvenous permanent pacemaker. A large soft tissue mass was seen in the right ventricular chamber around the pacing lead with echocardiography. Initially, this was thought to be caused by mural bacterial endocarditis based on hyperthermia, severe leukocytosis and the appearance of runs of ventricular tachycardia, the latter suggesting myocardial damage. While blood culture results were pending, antibiotics were administered without a positive effect. Due to clinical deterioration, the owner elected for euthanasia and a post-mortem examination confirmed a right ventricular thrombus and surrounding myocarditis, without signs of bacterial infection, and a massive pulmonary thromboembolism. We conclude that pulmonary thromboembolism should be considered in dogs with a cough that have an endocardial pacing lead implanted. Serial screening for proteinuria before and after implantation of an endocardial pacing lead would allow timely initiation of prophylactic antiplatelet therapy. Local myocarditis can develop secondary to an intracavitary thrombus, which can subsequently lead to runs of ventricular tachycardia.
PubMed: 38921984
DOI: 10.3390/vetsci11060237 -
Cells Jun 2024Exposure to cigarette smoke is known to induce disease during pregnancy. Recent evidence showed that exposure to secondhand smoke (SHS) negatively impacts fetal and...
Exposure to cigarette smoke is known to induce disease during pregnancy. Recent evidence showed that exposure to secondhand smoke (SHS) negatively impacts fetal and placental weights, leading to the development of intrauterine growth restriction (IUGR). Electronic cigarettes (eCigs) represent a phenomenon that has recently emerged, and their use is also steadily rising. Even so, the effects of SHS or eCigs during gestation remain limited. In the present study, we wanted to characterize the effects of SHS or eCig exposure at two different important gestational points during mouse pregnancy. C57/Bl6 mice were exposed to SHS or eCigs via a nose-only delivery system for 4 days (from 14.5 to 17.5 gestational days (dGA) or for 6 days (from 12.5 dGA to 17.5 dGA)). At the time of necropsy (18.5 dGA), placental and fetal weights were recorded, maternal blood pressure was determined, and a dipstick test to measure proteinuria was performed. Placental tissues were collected, and inflammatory molecules in the placenta were identified. Treatment with SHS showed the following: (1) a significant decrease in placental and fetal weights following four days of exposure, (2) higher systolic and diastolic blood pressure following six days of exposure, and (3) increased proteinuria after six days of exposure. Treatment with eCigs showed the following: (1) a significant decrease in placental weight and fetal weight following four or six days of exposure, (2) higher systolic and diastolic blood pressure following six days of exposure, and (3) increased proteinuria after six days of exposure. We also observed different inflammatory markers associated with the development of IUGR or PE. We conclude that the detrimental effects of SHS or eCig treatment coincide with the length of maternal exposure. These results could be beneficial in understanding the long-term effects of SHS or eCig exposure in the development of placental diseases.
Topics: Pregnancy; Female; Animals; Tobacco Smoke Pollution; Mice; Mice, Inbred C57BL; Placenta; Placenta Diseases; E-Cigarette Vapor; Maternal Exposure; Blood Pressure; Fetal Growth Retardation; Electronic Nicotine Delivery Systems
PubMed: 38920640
DOI: 10.3390/cells13121009 -
Immunopharmacology and Immunotoxicology Jun 2024Autoimmune dermatosis (AID) occurs when the body's immune system attacks skin or tissue, leading to various types of skin disorders or injuries. Recent studies show that...
OBJECTIVE
Autoimmune dermatosis (AID) occurs when the body's immune system attacks skin or tissue, leading to various types of skin disorders or injuries. Recent studies show that Janus kinases (JAKs) play critical roles in autoimmune diseases including AID by regulating multiple cytokine signaling pathways. CS12192, a novel JAK3/JAK1/TBK1 inhibitor, has been reported to exert ameliorative effects in rheumatoid arthritis. However, the efficacy of CS12192 on AID is undetermined. This study aims to investigate the therapeutic efficacy of CS12192 on psoriasis (PSO), systemic lupus erythematosus (SLE) and atopic dermatitis (AD) in mouse models.
METHODS
Interleukin-23 (IL-23)-induced PSO model, spontaneous SLE model of MRL/MpJ-Faslpr/J (MRL/lpr) mice, and oxazolone (OXA) and dinitrochlorobenzene (DNCB) induced murine AD models were used for the evaluation of curative effects of CS12192, respectively. The skin lesion, biochemical parameters, ear thickness, ear weight and histopathology were assessed accordingly.
RESULTS
In PSO model, mice treated with CS12192 show reduced ear thickness and ear weight as compared with vehicle. In SLE model, CS12192 ameliorates cutaneous parameters such as lymphadenectasis and skin lesion but not systematic parameters such as proteinuria concentration and score, serum dsDNA and BUN concentration. In AD models, CS12192 dose-dependently improves ear swelling and reduces histological scores, exerting equivalent efficacy with baricitinib, a marketed JAK1/JAK2 inhibitor. Our findings suggest that the novel JAK3/JAK1/TBK1 inhibitor CS12192 is potentially to alleviate autoimmune dermatosis.
PubMed: 38918174
DOI: 10.1080/08923973.2024.2373223 -
International Journal of... Apr 2024Chronic kidney disease (CKD) patients are at a high risk of tuberculosis (TB), with a relative risk of developing active TB of 10%-25%. Similarly, glomerular disease...
BACKGROUND
Chronic kidney disease (CKD) patients are at a high risk of tuberculosis (TB), with a relative risk of developing active TB of 10%-25%. Similarly, glomerular disease increases the risk of TB due to diminished glomerular filtration rate, proteinuria, and immunosuppression use. Further, the first-line anti-TB drugs are associated with acute kidney injury (AKI) even in patients with normal kidney functions.
METHODS
We retrospectively identified 10 patients hospitalized with unusual adverse effects of antituberculosis therapy (ATT) from 2013 to 2022.
RESULTS
We found three cases of AKI caused by rifampicin: acute interstitial nephritis, crescentic glomerulonephritis, and heme pigment-induced acute tubular necrosis. We observed rifampicin-induced accelerated hypertension and thrombocytopenia in two patients on maintenance hemodialysis. Isoniazid caused pancreatitis and cerebellitis in two CKD patients, respectively. In a CKD patient, we detected acute gout secondary to pyrazinamide-induced reduced uric acid excretion. We also observed cases of drug rash with eosinophilia and systemic symptoms and hypercalcemia due to immune reconstitution inflammatory syndrome in patients with glomerular disease on ATT. Immediate discontinuation of the offending drug, along with specific and supportive management, led to a recovery in all cases.
CONCLUSION
The adverse effects of ATT may be unusually severe and varied in kidney patients due to decreased renal elimination. Early recognition of these adverse effects and timely discontinuation of the offending drug is essential to limit morbidity and mortality.
Topics: Humans; Antitubercular Agents; Male; Retrospective Studies; Female; Middle Aged; Acute Kidney Injury; Aged; Adult; Renal Insufficiency, Chronic; Rifampin; Isoniazid; Nephritis, Interstitial; Tuberculosis; Pyrazinamide; Glomerulonephritis; Immune Reconstitution Inflammatory Syndrome
PubMed: 38916390
DOI: 10.4103/ijmy.ijmy_33_24 -
Frontiers in Nephrology 2024Various classes of targeted therapies have emerged in the last few years, which have revolutionized cancer treatment, and improved the prognosis and survival of cancer...
Various classes of targeted therapies have emerged in the last few years, which have revolutionized cancer treatment, and improved the prognosis and survival of cancer patients. Unfortunately, these agents have serious toxic effects on the kidneys. Some of the toxic effects are hypertension, acute kidney injury (AKI), and proteinuria. One interesting phenomenon that has emerged recently is pseudo-acute kidney injury due to the interference with the tubular secretion of creatinine by some of the targeted therapeutic agents. Understanding this physiology is needed to avoid unnecessary investigation and withholding of lifesaving chemo regimen. Alternative methods to assess renal function such as cystatin C-based estimated glomerular filtration rate (eGFR) can differentiate true AKI from pseudo-AKI. Here, we describe one such case of pseudo-AKI from cyclin-dependent kinase (CDK) 4/6 inhibitor, abemaciclib, which inhibits tubular secretion of creatinine. Using cystatin-C-based eGFR revealed pseudo-AKI in this case.
PubMed: 38915820
DOI: 10.3389/fneph.2024.1389562 -
BioRxiv : the Preprint Server For... Jun 2024Inverted formin-2 (INF2) gene mutations are among the most common causes of genetic focal segmental glomerulosclerosis (FSGS) with or without Charcot-Marie-Tooth (CMT)...
Inverted formin-2 (INF2) gene mutations are among the most common causes of genetic focal segmental glomerulosclerosis (FSGS) with or without Charcot-Marie-Tooth (CMT) disease. Recent studies suggest that INF2, through its effects on actin and microtubule arrangement, can regulate processes including vesicle trafficking, cell adhesion, mitochondrial calcium uptake, mitochondrial fission, and T-cell polarization. Despite roles for INF2 in multiple cellular processes, neither the human pathogenic R218Q INF2 point mutation nor the INF2 knock-out allele is sufficient to cause disease in mice. This discrepancy challenges our efforts to explain the disease mechanism, as the link between INF2-related processes, podocyte structure, disease inheritance pattern, and their clinical presentation remains enigmatic. Here, we compared the kidney responses to puromycin aminonucleoside (PAN) induced injury between R218Q INF2 point mutant knock-in and INF2 knock-out mouse models and show that R218Q INF2 mice are susceptible to developing proteinuria and FSGS. This contrasts with INF2 knock-out mice, which show only a minimal kidney phenotype. Co-localization and co-immunoprecipitation analysis of wild-type and mutant INF2 coupled with measurements of cellular actin content revealed that the R218Q INF2 point mutation confers a gain-of-function effect by altering the actin cytoskeleton, facilitated in part by alterations in INF2 localization. Differential analysis of RNA expression in PAN-stressed heterozygous R218Q INF2 point-mutant and heterozygous INF2 knock-out mouse glomeruli showed that the adhesion and mitochondria-related pathways were significantly enriched in the disease condition. Mouse podocytes with R218Q INF2, and an INF2-mutant human patient's kidney organoid-derived podocytes with an S186P INF2 mutation, recapitulate the defective adhesion and mitochondria phenotypes. These results link INF2-regulated cellular processes to the onset and progression of glomerular disease. Thus, our data demonstrate that gain-of-function mechanisms drive INF2-related FSGS and explain the autosomal dominant inheritance pattern of this disease.
PubMed: 38915495
DOI: 10.1101/2024.06.08.598088