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SIGNIFICANCE STATEMENT: The loss of integrity of the glomerular filtration barrier results in proteinuria that is often attributed to podocyte loss. Yet how damaged podocytes are lost remains unknown. Germline loss of murine podocyte-associated Hdac1 and Hdac2 ( Hdac1/2 ) results in proteinuria and collapsing glomerulopathy due to sustained double-stranded DNA damage. Hdac1/2 deletion induces loss of podocyte quiescence, cell cycle entry, arrest in G1, and podocyte senescence, observed both in vivo and in vitro . Through the senescence secretory associated phenotype, podocytes secrete proteins that contribute to their detachment. These results solidify the role of HDACs in cell cycle regulation and senescence, providing important clues in our understanding of how podocytes are lost following injury. BACKGROUND: Intact expression of podocyte histone deacetylases (HDAC) during development is essential for maintaining a normal glomerular filtration barrier because of its role in modulating DNA damage and preventing premature senescence. METHODS: Germline podocyte-specific Hdac1 and 2 ( Hdac1 / 2 ) double-knockout mice were generated to examine the importance of these enzymes during development. RESULTS: Podocyte-specific loss of Hdac1 / 2 in mice resulted in severe proteinuria, kidney failure, and collapsing glomerulopathy. Hdac1 / 2 -deprived podocytes exhibited classic characteristics of senescence, such as senescence-associated ß-galactosidase activity and lipofuscin aggregates. In addition, DNA damage, likely caused by epigenetic alterations such as open chromatin conformation, not only resulted in podocyte cell-cycle entry as shown in vivo by Ki67 expression and by FUCCI-2aR mice, but also in p21-mediated cell-cycle arrest. Through the senescence secretory associated phenotype, the damaged podocytes secreted proinflammatory cytokines, growth factors, and matrix metalloproteinases, resulting in subsequent podocyte detachment and loss, evidenced by senescent podocytes in urine. CONCLUSIONS: Hdac1 / 2 plays an essential role during development. Loss of these genes in double knockout mice leads to sustained DNA damage and podocyte senescence and loss.
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Ciclo Celular , Histona Desacetilasa 1 , Podocitos , Animales , Ratones , Histona Desacetilasa 1/metabolismo , Ratones Noqueados , Podocitos/metabolismo , Proteinuria/etiologíaRESUMEN
Acute kidney injury (AKI) contributes to the development of acute lung injury (ALI) via proinflammatory responses. We hypothesized that activation of a nicotinic acetylcholine receptor (nAChR), which exerts cholinergic anti-inflammatory effects on macrophages, could reduce ALI after AKI. We aimed to determine whether nAChR agonists could reduce ALI after AKI and which macrophages in the lung or spleen contribute to the improvement of ALI by nAChR agonists. We induced AKI in male mice by unilateral ischemia-reperfusion injury (IRI) with contralateral nephrectomy and administered nAChR agonists in three experimental settings: 1) splenectomy, 2) deletion of splenic macrophages and systemic mononuclear phagocytes via intravenous administration of clodronate liposomes, and 3) alveolar macrophage deletion via intratracheal administration of clodronate liposomes. Treatment with GTS-21, an α7nAChR-selective agonist, significantly reduced the levels of circulating IL-6, a key proinflammatory cytokine, and lung chemokine (C-X-C motif) ligand (CXCL)1 and CXCL2 and neutrophil infiltration, and Evans blue dye (EBD) vascular leakage increased after renal IRI. In splenectomized mice, GTS-21 did not reduce circulating IL-6 and lung CXCL1 and CXCL2 levels and neutrophil infiltration, and EBD vascular leakage increased after renal IRI. In mice depleted of splenic macrophages and systemic mononuclear phagocytes, GTS-21 treatment did not reduce lung neutrophil infiltration, and EBD vascular leakage increased after renal IRI. In mice depleted of alveolar macrophages, GTS-21 treatment significantly reduced lung neutrophil infiltration, and EBD vascular leakage increased after renal IRI. Our findings show that nAChR agonist reduces circulating IL-6 levels and acute lung injury after renal IRI by acting on splenic macrophages.NEW & NOTEWORTHY Acute lung injury associated with acute kidney injury contributes to high mortality. This study showed, for the first time, that nicotinic acetylcholine receptor agonists reduced circulating IL-6 and ALI after renal ischemia-reperfusion injury in mice. These effects of α7nAChR agonist were eliminated in both splenectomized and splenic macrophage (including systemic mononuclear phagocyte)-depleted mice but not alveolar macrophage-depleted mice. nAChR agonist could reduce ALI after AKI via splenic macrophages and provide a novel strategy in AKI.
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Lesión Renal Aguda , Lesión Pulmonar Aguda , Receptores Nicotínicos , Daño por Reperfusión , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/prevención & control , Animales , Ácido Clodrónico , Interleucina-6 , Liposomas , Macrófagos , Masculino , Ratones , Ratones Endogámicos C57BL , Agonistas Nicotínicos , Daño por Reperfusión/complicaciones , Daño por Reperfusión/tratamiento farmacológico , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Toll-like receptor 9 (TLR9), which is activated by endogenously released mtDNA during sepsis, contributes to the development of polymicrobial septic acute kidney injury (AKI). However, downstream factors of TLR9 to AKI remain unknown. We hypothesized that IL-17A activated by TLR9 may play a critical role in septic AKI development. To determine the effects of TLR9 on IL-17A production in septic AKI, we used a cecal ligation and puncture (CLP) model in Tlr9 knockout (Tlr9KO) mice and wild-type (WT) littermates. We also investigated the pathway from TLR9 activation in dendritic cells (DCs) to IL-17A production by γδT cells in vitro. To elucidate the effects of IL-17A on septic AKI, Il-17a knockout (Il-17aKO) mice and WT littermates were subjected to CLP. We further investigated the relationship between the TLR9-IL-17A axis and septic AKI by intravenously administering recombinant IL-17A or vehicle into Tlr9KO mice and assessing kidney function. IL-17A levels in both plasma and the peritoneal cavity and mRNA levels of IL-23 in the spleen were significantly higher in WT mice after CLP than in Tlr9KO mice. Bone marrow-derived DCs activated by TLR9 induced IL-23 and consequently promoted IL-17A production in γδT cells in vitro. Knockout of Il-17a improved survival, functional and morphological aspects of AKI, and splenic apoptosis after CLP. Exogenous IL-17A administration aggravated CLP-induced AKI attenuated by knockout of Tlr9. TLR9 in DCs mediated IL-17A production in γδT cells during sepsis and contributed to the development of septic AKI.
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Lesión Renal Aguda/metabolismo , Interleucina-17/metabolismo , Sepsis/metabolismo , Receptor Toll-Like 9/metabolismo , Lesión Renal Aguda/patología , Animales , Apoptosis , Citocinas/metabolismo , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Interleucina-17/genética , Interleucina-17/farmacología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Ratones , Ratones Noqueados , Sepsis/patología , Bazo/metabolismo , Receptor Toll-Like 9/genéticaRESUMEN
INTRODUCTION: Patients without detectable serum antiglomerular basement membrane (GBM) antibodies but with GBM staining for immunoglobulins (Ig), absence of a crescentic phenotype, mild renal insufficiency, and absence of pulmonary hemorrhage have atypical anti-GBM diseases. We report the case of a 64-year-old man with slowly progressive glomerulonephritis. CASE HISTORY: A 64-year-old Peruvian man presented with persistent microscopic hematuria, proteinuria of 2.1 g/g creatinine (Cr), serum Cr 1.00 mg/dL, and C-reactive protein 0.80 mg/dL. Renal biopsy revealed necrotizing glomerulonephritis with 39% cellular crescent formation and diffuse segmental endocapillary proliferation. He had linear staining of monoclonal IgG1-κ in the capillary walls but no detectable serum anti-GBM antibodies. Because renal dysfunction was slowly progressing, steroid monotherapy was initiated, and serum Cr level decreased from 1.48 to 1.13 mg/dL. However, serum Cr increased again to 1.35 mg/dL owing to active glomerular damage with crescent formation and endocapillary proliferation, confirmed by the second renal biopsy at 9 months after therapy. Renal function improved after cyclophosphamide therapy. CONCLUSION: We described an atypical variant of anti-GBM disease due to monoclonal IgG1-κ. Unlike usual atypical anti-GBM disease cases, we observed crescent formation in our patient. Further investigations are needed to identify the cause of nondetectable serum anti-GBM antibodies and to describe the causal relationships between clinicopathological features and the pattern of IgG subclass and light chain in atypical anti-GBM disease.
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Enfermedad por Anticuerpos Antimembrana Basal Glomerular/inmunología , Glomerulonefritis/inmunología , Inmunoglobulina G/sangre , Cadenas kappa de Inmunoglobulina/sangre , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/patología , Autoanticuerpos/sangre , Glomerulonefritis/patología , Humanos , Masculino , Persona de Mediana Edad , NecrosisAsunto(s)
Antituberculosos/uso terapéutico , Glomerulonefritis por IGA/tratamiento farmacológico , Enfermedades Pulmonares/tratamiento farmacológico , Complejo Mycobacterium avium/efectos de los fármacos , Infección por Mycobacterium avium-intracellulare/tratamiento farmacológico , Prednisolona/administración & dosificación , Rifampin/uso terapéutico , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIM: This study aimed to investigate the association between changes in body composition, glycated hemoglobin, and lipid ratio during the treatment of patients with type 2 diabetes mellitus (T2DM). METHODS: This retrospective analysis used data from outpatients with T2DM who had confirmed body composition and measured laboratories at administration and after treatment. The baseline characteristics and prescribed treatment were collected. The total cholesterol/high-density lipoprotein cholesterol (HDL) ratio, low-density lipoprotein cholesterol (LDL)/HDL ratio, and triglyceride-glucose (TyG) index were also calculated. RESULTS: A total of 207 patients (mean patient age, 62.0 ± 13.7 years; 68.1 % males) were enrolled. Fat mass index (FMI) changes correlated with the changes in the lipid ratio, whereas skeletal muscle mass index (SMI) changes inversely correlated with glycated hemoglobin (HbA1c) changes. Multiple regression analysis showed that changes in LDL/HDL and TyG correlated with FMI changes (t = 2.388, p = 0.017, t = 2.022, p = 0.044). Conversely, HbA1c changes correlated with SMI changes (t = -2.552, p = 0.011). CONCLUSION: In patients with T2DM, increased SMI was involved in glycemic efficacy, and FMI changes were associated with LDL/HDL and TyG.
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Diabetes Mellitus Tipo 2 , Masculino , Humanos , Persona de Mediana Edad , Anciano , Femenino , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada , Glucemia , Estudios Retrospectivos , Triglicéridos , LDL-Colesterol , HDL-Colesterol , Glucosa , Músculo EsqueléticoRESUMEN
Since the seminal discovery of the trypanolytic, exonic variants in apolipoprotein L1 (APOL1) and their association with kidney disease in individuals of recent African ancestry, a wide body of research has emerged offering key insights into the mechanisms of disease. Importantly, the podocyte has become a focal point for our understanding of how risk genotype leads to disease, with activation of putative signaling pathways within the podocyte identified as playing a causal role in podocytopathy, FSGS, and progressive renal failure. However, the complete mechanism of genotype-to-phenotype progression remains incompletely understood in APOL1-risk individuals. An emerging body of evidence reports more than podocyte-intrinsic expression of APOL1 risk variants is needed for disease to manifest. This article reviews the seminal data and reports which placed the podocyte at the center of our understanding of APOL1-FSGS, as well as the evident shortcomings of this podocentric paradigm. We examine existing evidence for environmental and genetic factors that may influence disease, drawing from both clinical data and APOL1's fundamental role as an immune response gene. We also review the current body of data for APOL1's impact on nonpodocyte cells, including endothelial cells, the placenta, and immune cells in both a transplant and native setting. Finally, we discuss the implications of these emerging data and how the paradigm of disease might evolve as a result.
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Glomeruloesclerosis Focal y Segmentaria , Humanos , Glomeruloesclerosis Focal y Segmentaria/genética , Apolipoproteína L1/genética , Factores de Riesgo , Células Endoteliales , GenotipoRESUMEN
The progression of proteinuric kidney diseases is associated with podocyte loss, but the mechanisms underlying this process remain unclear. Podocytes reenter the cell cycle to repair double-stranded DNA breaks. However, unsuccessful repair can result in podocytes crossing the G1/S checkpoint and undergoing abortive cytokinesis. In this study, we identified Pfn1 as indispensable in maintaining glomerular integrity - its tissue-specific loss in mouse podocytes resulted in severe proteinuria and kidney failure. Our results suggest that this phenotype is due to podocyte mitotic catastrophe (MC), characterized histologically and ultrastructurally by abundant multinucleated cells, irregular nuclei, and mitotic spindles. Podocyte cell cycle reentry was identified using FUCCI2aR mice, and we observed altered expression of cell-cycle associated proteins, such as p21, p53, cyclin B1, and cyclin D1. Podocyte-specific translating ribosome affinity purification and RNA-Seq revealed the downregulation of ribosomal RNA-processing 8 (Rrp8). Overexpression of Rrp8 in Pfn1-KO podocytes partially rescued the phenotype in vitro. Clinical and ultrastructural tomographic analysis of patients with diverse proteinuric kidney diseases further validated the presence of MC podocytes and reduction in podocyte PFN1 expression within kidney tissues. These results suggest that profilin1 is essential in regulating the podocyte cell cycle and its disruption leads to MC and subsequent podocyte loss.
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Enfermedades Renales , Podocitos , Profilinas , Animales , Humanos , Ratones , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Muerte Celular/genética , Enfermedades Renales/metabolismo , Glomérulos Renales/patología , Podocitos/patología , Profilinas/genética , Proteinuria/patologíaRESUMEN
Acute kidney injury (AKI) causes glucose and protein metabolism abnormalities that result in muscle wasting, thereby affecting the long-term prognosis of critical illness survivors. Here, we examined whether early intervention with treadmill exercise and branched-chain amino acids (BCAA) can prevent AKI-related muscle wasting and reduced physical performance in mice. Unilateral 15 min ischemia-reperfusion injury was induced in contralateral nephrectomized mice, and muscle histological and physiological changes were assessed and compared with those of pair-fed control mice, since AKI causes severe anorexia. Mice exercised for 30 min each day and received oral BCAA for 7 days after AKI insult. By day 7, ischemic AKI significantly decreased wet weight, myofiber cross-sectional area, and central mitochondrial volume density of the anterior tibialis muscle, and significantly reduced maximal exercise time. Regular exercise and BCAA prevented AKI-related muscle wasting and low physical performance by suppressing myostatin and atrogin-1 mRNA upregulation, and restoring reduced phosphorylated Akt and PGC-1α mRNA expression in the muscle. Ischemic AKI induces muscle wasting by accelerating muscle protein degradation and reducing protein synthesis; however, we found that regular exercise and BCAA prevented AKI-related muscle wasting without worsening kidney damage, suggesting that early rehabilitation with nutritional support could prevent AKI-related muscle wasting.
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Lesión Renal Aguda/complicaciones , Aminoácidos de Cadena Ramificada/uso terapéutico , Músculo Esquelético/fisiopatología , Condicionamiento Físico Animal/métodos , Síndrome Debilitante/terapia , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias Musculares/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , Proteolisis , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Ligasas SKP Cullina F-box/genética , Proteínas Ligasas SKP Cullina F-box/metabolismo , Síndrome Debilitante/tratamiento farmacológico , Síndrome Debilitante/etiologíaRESUMEN
We herein report the case of a hemodialysis patient whose response to an erythropoiesis-stimulating agent (ESA) improved following the resection of thyroid cancer. Her hemoglobin level remained below 7 g/dL, despite the use of ESA. During the search for the causes of her hyporesponsiveness to ESA, papillary thyroid cancer and aceruloplasminemia were found. The existence of other potential causes, such as iron deficiency, infectious disease, severe hyperparathyroidism and malnutrition were ruled out. Following the resection of the thyroid cancer tumor, her hemoglobin level increased to 10.2 g/dL over a period of 4 months. This is the first report to demonstrate the resolution of hyporesponsiveness to ESA following the resection of a malignant tumor.
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Carcinoma/complicaciones , Carcinoma/cirugía , Ceruloplasmina/deficiencia , Hematínicos/uso terapéutico , Trastornos del Metabolismo del Hierro/complicaciones , Enfermedades Neurodegenerativas/complicaciones , Diálisis Renal , Neoplasias de la Tiroides/complicaciones , Neoplasias de la Tiroides/cirugía , Anemia/etiología , Carcinoma/diagnóstico , Carcinoma Papilar , Femenino , Hematínicos/administración & dosificación , Hemoglobinas/análisis , Humanos , Persona de Mediana Edad , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/diagnósticoRESUMEN
We herein report a case of primary adrenal lymphoma with severe hyponatremia. The patient was admitted for an evaluation of severe hyponatremia and an enlarged bilateral adrenal mass, which were found in a previous examination for causes of general fatigue and anorexia. Laboratory data, including the serum levels of sodium (115 mEq/L), osmolality (239 mOsm/kgH2O), ADH (5.8 pg/mL), cortisol (11.6 µg/dL), free T3 (2.42 pg/mL), urinary Na (117 mEq/L) and urine osmolality (490 mOsm/kgH2O), fulfilled the diagnostic criteria for the syndrome of inappropriate secretion of ADH (SIADH). An abdominal computed tomography scan revealed a large bilateral adrenal mass. A biopsy of the enlarged left adrenal mass revealed diffuse large B cell lymphoma, which was negative for ADH protein. Hydrocortisone treatment normalized the patient's body temperature and serum sodium concentration. In this case, hyponatremia developed when both adrenal glands were involved and was normalized with hydrocortisone. These findings suggest that adrenal insufficiency was the cause of hyponatremia, although the basal serum cortisol was normal. The current case suggests that the administration of hydrocortisone is recommended if suspicious clinical signs or symptoms are found in severe hyponatremia, even if hyponatremia is associated with a normal serum cortisol level and fulfills the diagnostic criteria for SIADH.
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We apply a simple Brownian ratchet model to an artificial molecular rotary system mounted in a biological membrane, in which the rotor always maintains unidirectional rotation in response to a linearly polarized weak ac field. Because the rotor and stator compose a ratchet system, we describe the motion of the rotor tip with the Langevin equation for a particle in a two-dimensional three-tooth ratchet potential of threefold symmetry. Unidirectional rotation can be induced under the field and optimized by stochastic resonance, wherein the mean angular momentum (MAM) of the rotor exhibits a bell-shaped curve for the noise strength. We obtain analytical expressions for the MAM and power loss from the corresponding Fokker-Planck equation, via a Markov transition model for coarse-grained states (six-state model). The MAM expression reveals a significant effect depending on the chirality of the ratchet potential: in achiral cases, the MAM approximately vanishes with respect to the polarization angle φ of the field; in chiral cases, the MAM does not crucially depend on φ, but depends on the direction of the ratchet; i.e., the parity of the unidirectional rotation is inherent in the ratchet structure. This feature is useful for artificial rotary systems to maintain robust unidirectional rotation independent of the mounting condition.