RESUMEN
A major complication of heat-related illness is the development of acute kidney injury (AKI) and damage to kidney tubular cells. Because kidney tubular cells use fatty acids as a major energy source, impaired fatty acid oxidation (FAO) may be associated with kidney injury due to heat stress. Carnitine is essential in the transportation of fatty acid into mitochondria for FAO. To date, there has been little attention given to the role of carnitine in heat-related illness and AKI. To evaluate the relationship between carnitine inadequacy and heat-related illness severity or AKI, we examined serum carnitine levels in patients with heat-related illness. We also used heat-stressed mice to investigate the effect of l-carnitine pretreatment on various kidney functions such as mitochondrial activity, proinflammatory changes in kidney macrophages, and histological damage. We observed an elevation in serum acylcarnitine levels, indicating carnitine insufficiency in patients with severe heat-related illness and/or AKI. l-Carnitine pretreatment ameliorated ATP production in murine tubular cell mitochondria and prevented a change in the kidney macrophage population dynamics observed in AKI: a decrease in tissue-resident macrophages, influx of bone marrow-derived macrophages, and change toward proinflammatory M1 polarization. In conclusion, carnitine insufficiency may be closely associated with severe heat-related illness and related AKI. Enhancement of the FAO pathway by l-carnitine pretreatment may prevent heat stress-induced AKI by restoring mitochondrial function.NEW & NOTEWORTHY Enhancing fatty acid oxidation (FAO) after acute kidney injury (AKI) improves renal outcomes. This report shows that carnitine insufficiency, which could inhibit FAO, correlates to severe heat-related illness and AKI in a clinical study. We also demonstrate that administering l-carnitine to mice improves mitochondrial respiratory function and prevents deleterious changes in renal macrophage, resulting in improved renal outcomes of heat-induced AKI. l-Carnitine may be an effective preventive treatment for severe heat-related illness and related AKI.
Asunto(s)
Lesión Renal Aguda , Humanos , Ratones , Animales , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/prevención & control , Riñón/metabolismo , Carnitina/farmacología , Carnitina/metabolismo , Carnitina/uso terapéutico , Mitocondrias/metabolismo , Respuesta al Choque Térmico , Ácidos Grasos/metabolismoRESUMEN
BACKGROUND: Since heatstroke-induced acute kidney injury (AKI) can progress to chronic kidney disease, it would be useful to detect heatstroke-induced AKI and severe heat-related illness in the early phase. We studied the epidemiology of heat-related illness among patients in the Japanese Ground Self-Defense Force and evaluated the relationship between heat-related illness severity and early urinary biomarkers for AKI. METHODS: We enrolled patients who were diagnosed with heat-related illness at the Self-Defense Force Fuji Hospital from 1 May to 30 September 2020. We compared the urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), liver fatty acid-binding protein (L-FABP), N-acetyl-ß-D-glucosaminidase (NAG) and ß2-microglobulin levels according to the severity of heat-related illness as defined by positive scores for the Japanese Association of Acute Medicine Heatstroke Working Group (JAAM-HS-WG) criteria (0, mild; 1, moderate; ≥2, severe). RESULTS: Of the 44 patients, kidney injury, defined as serum creatinine (sCr) ≥1.2 mg/dL, was seen in 9 (20.5%) patients. Urinary NAG, NGAL and L-FABP levels were significantly higher in the ≥2 JAAM-HS-WG criteria group than in the 0 group. Furthermore, urinary L-FABP levels were positively correlated with sCr levels. In contrast, the urinary KIM-1 levels showed the best correlation with serum cystatin C (sCysC) among these biomarkers. CONCLUSIONS: We conclude even mild to moderate heatstroke could lead to AKI. Urinary L-FABP is useful for detecting heatstroke-induced AKI and patients with severe heat-related illness requiring immediate treatment. Urinary KIM-1 may detect heatstroke-induced AKI in terms of sCysC, although it was not related to the severity of heat-related illness.
Asunto(s)
Lesión Renal Aguda , Golpe de Calor , Humanos , Lipocalina 2 , Lipocalinas , Pueblos del Este de Asia , Calor , Biomarcadores , Lesión Renal Aguda/diagnóstico , Riñón , Proteínas de Unión a Ácidos Grasos/orinaRESUMEN
Heatstroke can cause acute kidney injury (AKI), which reportedly progresses to chronic kidney disease. Kidney macrophages may be involved in such injury. Although heat acclimation (HA) provides thermal resilience, its renoprotective effect and mechanism remain unclear. To investigate heat stress-induced kidney injuries in mice and the mitigating effect of HA on them, male C57/BL6J mice were exposed to heat stress (40°C, 1 h) with or without 5-day HA (38°C, 3 h/day) prior to heat stress. Heat stress damaged kidney proximal tubules with an elevation of urinary kidney injury molecule-1. Kidney fibrosis was observed on day 7 and correlated with urinary kidney injury molecule-1 levels on day 3. Kidney resident macrophages decreased on day 1, whereas the number of infiltrating macrophages in the kidney did not change. Both subsets of macrophages polarized to the proinflammatory M1 phenotype on day 1; however, they polarized to the anti-inflammatory M2 phenotype on day 7. HA significantly ameliorated heat stress-induced proximal tubular damage and kidney fibrosis. HA substantially increased heat shock protein 70 expression in the tubules before heat stress and reduced the elevation of cleaved caspase-3 expression after heat stress. HA also induced heat shock protein 70 expression of resident macrophages and prevented heat stress-induced changes in both subsets of kidney macrophages. These results provide pathophysiological data supporting the renoprotective effect of HA. Further studies are needed to confirm that HA can prevent kidney damage due to heat stress in humans.NEW & NOTEWORTHY Heat stress could induce acute kidney injury. Although heat acclimation (HA) reportedly provides thermal tolerance, its effect on heat stress-induced kidney damage remains unclear. This study showed that 5-day HA ameliorates mouse kidney tubular damage and subsequent fibrosis caused by heat stress. It also demonstrated that HA enhances intracellular heat shock protein 70 expression in tubular cells and prevents a decrease in kidney resident macrophages, which explains the renoprotective effect of HA.
Asunto(s)
Lesión Renal Aguda , Trastornos de Estrés por Calor , Aclimatación/fisiología , Lesión Renal Aguda/genética , Lesión Renal Aguda/prevención & control , Animales , Fibrosis , Proteínas HSP70 de Choque Térmico/metabolismo , Trastornos de Estrés por Calor/patología , Respuesta al Choque Térmico , Riñón/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
OBJECTIVES: Up to 0.3% of Japanese have hypouricaemia. Most cases appear to result from a hereditary disease, renal hypouricaemia (RHUC), which causes exercise-induced acute kidney injury and urolithiasis. However, to what extent RHUC accounts for hypouricaemia is not known. We therefore investigated its frequency and evaluated its risks by genotyping a general Japanese population. METHODS: A cohort of 4993 Japanese was examined by genotyping the non-functional variants R90H (rs121907896) and W258X (rs121907892) of URAT1/SLC22A12, the two most common causative variants of RHUC in Japanese. RESULTS: Participants' fractional excretion of uric acid and risk allele frequencies markedly increased at lower serum uric acid (SUA) levels. Ten participants (0.200%) had an SUA level ≤2.0 mg/dl and nine had R90H or W258X and were likely to have RHUC. Logistic regression analysis revealed these URAT1 variants to be significantly and independently associated with the risk of hypouricaemia and mild hypouricaemia (SUA ≤3.0 mg/dl) as well as sex, age and BMI, but these URAT1 variants were the only risks in the hypouricaemia population (SUA ≤2.0 mg/dl). W258X was only a risk in males with SUA ≤3.0 mg/dl. CONCLUSION: Our study accurately reveals the prevalence of RHUC and provides genetic evidence for its definition (SUA ≤2.0 mg/dl). We also show that individuals with SUA ≤3.0 mg/dl, especially males, are prone to RHUC. Our findings will help to promote a better epidemiological understanding of RHUC as well as more accurate diagnosis, especially in males with mild hypouricaemia.
Asunto(s)
Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética , Defectos Congénitos del Transporte Tubular Renal/genética , Cálculos Urinarios/genética , Femenino , Variación Genética , Genotipo , Humanos , Japón/epidemiología , Masculino , Defectos Congénitos del Transporte Tubular Renal/epidemiología , Cálculos Urinarios/epidemiologíaRESUMEN
Control of lymphocyte infiltration in kidney is a potential therapeutic strategy for lupus nephritis, considering that control of lymphocyte migration by sphingosine 1 phosphate has been implicated in inflammation-related pathology. The peptide inhibitor of the transendothelial migration (PEPITEM)/cadherin (CDH) 15 axis was recently reported to promote sphingosine 1 phosphate secretion. In this study, we investigated whether CDH15 is expressed in the kidney of MRL/lpr mice and whether lymphocyte infiltration is suppressed by exogenously administered PEPITEM. Mice (18 wk old) were randomized into 4-wk treatment groups that received PEPITEM or PBS encapsulated in dipalmitoylphosphatidylcholine liposomes. Enlargement of the kidney, spleen, and axillary lymph nodes was suppressed by PEPITEM treatment, which also blocked infiltration of double-negative T lymphocytes into the kidney and glomerular IgG/C3 deposition, reduced proteinuria, and increased podocyte density. Immunohistochemical analysis revealed that the PEPITEM receptor CDH15 was expressed on vascular endothelial cells of glomeruli and kidney arterioles, skin, and peritoneum in lupus mice at 22 wk of age but not in 4-wk-old mice. These results suggest that PEPITEM inhibits lymphocyte migration and infiltration into the kidney, thereby preserving the kidney structure and reducing proteinuria. Thus, PEPITEM administration may be considered as a potential therapeutic tool for systemic lupus erythematosus.
Asunto(s)
Cadherinas/metabolismo , Glomerulonefritis/tratamiento farmacológico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Péptidos/farmacología , Linfocitos T/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Femenino , Glomerulonefritis/inmunología , Inyecciones Subcutáneas , Lupus Eritematoso Sistémico/inmunología , Ratones , Ratones Endogámicos MRL lpr , Péptidos/administración & dosificación , Linfocitos T/inmunología , Migración Transendotelial y Transepitelial/efectos de los fármacos , Migración Transendotelial y Transepitelial/inmunologíaRESUMEN
INTRODUCTION: In diabetic nephropathy (DN), mitochondrial dysfunction and leakage of mitochondrial DNA (mtDNA) are caused by the downregulation of superoxide dismutase 2 (SOD2). mtDNA induces the activation of Toll-like receptor (TLR) 9, which is present in macrophages (Mφs), and triggers their activation. METHODS: We orally administered L-carnitine, which exerts protective effects on the mitochondria, to obesity-induced DN (db/db) mice for 8 weeks. We then investigated the effects of L-carnitine on kidney mitochondrial reactive oxygen species (mtROS) production, circulating mtDNA content, and kidney CD11bhigh/CD11blow Mφ functions. RESULTS: In db/db mice, mtROS production increased in proximal tubular cells and kidney CD11blow Mφs; both Mφ types showed enhanced TLR9 expression. L-Carnitine treatment suppressed mtROS production in both proximal tubular cells and CD11blow Mφs (p < 0.01), with improved SOD2 expression in the kidney (p < 0.01), decreased circulating mtDNA content, and reduced albuminuria. Moreover, it suppressed Mφ infiltration into kidneys and reduced TLR9 expression in Mφs (p < 0.01), thereby lowering tumor necrosis factor-α production in CD11bhigh Mφs (p < 0.05) and ROS production by CD11blow Mφs (p < 0.01). Collectively, these changes alleviated DN symptoms. CONCLUSION: The positive effects of L-carnitine on DN suggest its potential as a novel therapeutic agent against obesity-linked DN.
Asunto(s)
Diabetes Mellitus , Nefropatías Diabéticas , Animales , Carnitina/farmacología , Carnitina/uso terapéutico , ADN Mitocondrial/metabolismo , ADN Mitocondrial/farmacología , ADN Mitocondrial/uso terapéutico , Diabetes Mellitus/metabolismo , Nefropatías Diabéticas/patología , Riñón/patología , Macrófagos/metabolismo , Ratones , Mitocondrias/metabolismo , Obesidad/metabolismo , Receptor Toll-Like 9/metabolismoRESUMEN
The pathogenesis of diabetic nephropathy (DN) is related to macrophage (Mφ) recruitment to the kidneys, tumor necrosis factor-α (TNF-α) production, and oxidative stress. Toll-like receptor 9 (TLR9) activation is reportedly involved in systemic inflammation, and it exacerbates this condition in metabolic syndrome. Therefore, we hypothesized that TLR9 plays a role in the pathogenesis of DN. Two subsets of kidney Mφs in DN model (db/db) mice were analyzed using flow cytometry to evaluate their distribution and TLR9 expression and function. Mice were administered the CCR2 antagonist INCB3344 for 8 wk; changes in Mφ distribution and function and its therapeutic effects on DN pathology were examined. Bone marrow-derived CD11bhigh (BM-Mφ) and tissue-resident CD11blow Mφs (Res-Mφ) were identified in the mouse kidneys. As DN progressed, the BM-Mφ number, TLR9 expression, and TNF-α production increased significantly. In Res-Mφs, reactive oxygen species (ROS) production and phagocytic activity were enhanced. INCB3344 decreased albuminuria, serum creatinine level, BM-Mφ abundance, TLR9 expression, and TNF-α production by BM-Mφs and ROS production by Res-Mφs. Both increased activation of BM-Mφ via TLR9 and TNF-α production and increased ROS production by Res-Mφs were involved in DN progression. Thus, inactivating Mφs and their TLR9 expression by INCB3344 is a potential therapeutic strategy for DN.NEW & NOTEWORTHY We classified kidney macrophages (Mφs) into bone marrow-derived Mφs (BM-Mφs) expressing high CD11b and tissue-specific resident Mφ (Res-Mφs) expressing low CD11b. In diabetic nephropathy (DN) model mice, Toll-like receptor 9 (TLR9) expression and TNF-α production via TLR9 activation in BM-Mφs and ROS production in Res-Mφs were enhanced. Furthermore, CCR2 antagonist suppressed the kidney infiltration of BM-Mφs and their function and the ROS production by Res-Mφs, with concomitant TLR9 suppression. Our study presents a new therapeutic strategy for DN.
Asunto(s)
Nefropatías Diabéticas/tratamiento farmacológico , Riñón/efectos de los fármacos , Macrófagos/efectos de los fármacos , Pirrolidinas/farmacología , Receptores CCR2/antagonistas & inhibidores , Receptor Toll-Like 9/metabolismo , Animales , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/inmunología , Nefropatías Diabéticas/metabolismo , Modelos Animales de Enfermedad , Riñón/inmunología , Riñón/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Fagocitosis/efectos de los fármacos , Fenotipo , Especies Reactivas de Oxígeno/metabolismo , Receptores CCR2/metabolismo , Receptores de Leptina/genética , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Recent studies indicate that erythropoietin (EPO) is present in many areas of the brain and is active in the restoration of impaired neurons. In this study, we examined the presence of EPO and its role in bulbospinal neurons in the rostral ventrolateral medulla (RVLM). Hypoxia is often accompanied by a high blood pressure (BP). We hypothesized that EPO is produced in response to hypoxia in RVLM neurons and then activates them. To investigate whether RVLM neurons are sensitive to EPO, we examined the changes in the membrane potentials (MPs) of bulbospinal RVLM neurons using the whole cell patch-clamp technique during superfusion with EPO. A brainstem-spinal cord preparation was used for the experiments. EPO depolarized the RVLM neurons, and soluble erythropoietin receptor (SEPOR), an antagonist of EPO, hyperpolarized them. Furthermore, hypoxia-depolarized RVLM neurons were significantly hyperpolarized by SEPOR. In histological examinations, the EPO-depolarized RVLM neurons showed the presence of EPO receptor (EPOR). The RVLM neurons that possessed EPORs showed the presence of EPO and hypoxia-inducible factor (HIF)-2α. We also examined the levels of HIF-2α and EPO messenger RNA (mRNA) in the ventral sites of the medullas (containing RVLM areas) in response to hypoxia. The levels of HIF-2α and EPO mRNA in the hypoxia group were significantly greater than those in the control group. These results suggest that EPO is produced in response to hypoxia in RVLM neurons and causes a high BP via the stimulation of those neurons. EPO may be one of the neurotransmitters produced by RVLM neurons during hypoxia.
Asunto(s)
Eritropoyetina/metabolismo , Bulbo Raquídeo/metabolismo , Neuronas/metabolismo , Potenciales de Acción , Animales , Animales Recién Nacidos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Presión Sanguínea , Hipoxia de la Célula , Eritropoyetina/genética , Eritropoyetina/farmacología , Hipertensión/etiología , Hipertensión/metabolismo , Hipertensión/fisiopatología , Hipoxia/complicaciones , Hipoxia/metabolismo , Hipoxia/fisiopatología , Técnicas In Vitro , Bulbo Raquídeo/efectos de los fármacos , Bulbo Raquídeo/fisiopatología , Neuronas/efectos de los fármacos , Ratas Wistar , Receptores de Eritropoyetina/agonistas , Receptores de Eritropoyetina/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: Podocyte phospholipase A2 receptor (PLA2R) is a major target antigen in idiopathic adult membranous nephropathy (MN). Histological PLA2R staining in the renal tissue has proven to be useful for the detection of idiopathic MN. However, glomerular PLA2R deposits have also been recently observed in several patients with secondary MN, such as hepatitis B virus-associated, hepatitis C virus-associated, and neoplasm-associated MN. Certain inflammatory environments have been suggested to lead to abnormal expression of PLA2R epitopes, with the resulting production of PLA2R autoantibodies. CASE PRESENTATION: We report two patients diagnosed with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis with MN-lesions, in whom ANCA titers for myeloperoxidase (MPO) were persistently positive. The first patient was a 52-years-old man who presented with interstitial pneumonitis. Microscopic hematuria and proteinuria were found when the interstitial pneumonitis became more severe. Renal biopsy findings yielded a diagnosis of ANCA-associated glomerulonephritis (mixed class) with MN-lesions. The second patient was a 63-years-old woman who had been treated for relapsing polychondritis. Her renal tissue showed evidence of focal ANCA-associated glomerulonephritis with MN-lesions. Interestingly, both MPO and PLA2R were detected in the glomerular subepithelial deposits of both patients. Immunoglobulin G (IgG) 1 and IgG2 were positive in the glomeruli of patient 2, and all subclasses of IgGs were positive in patient 1. CONCLUSION: The present cases suggest that ANCA-associated glomerulonephritis could expose PLA2R, leading to the development of MN-lesions.
Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/metabolismo , Glomerulonefritis Membranosa/metabolismo , Poliangitis Microscópica/metabolismo , Peroxidasa/metabolismo , Receptores de Fosfolipasa A2/metabolismo , Anticuerpos Anticitoplasma de Neutrófilos/análisis , Femenino , Glomerulonefritis Membranosa/complicaciones , Glomerulonefritis Membranosa/diagnóstico , Humanos , Masculino , Poliangitis Microscópica/complicaciones , Poliangitis Microscópica/diagnóstico , Persona de Mediana Edad , Peroxidasa/análisis , Receptores de Fosfolipasa A2/análisisRESUMEN
A 74-year-old woman with liver cirrhosis and chronic kidney disease (CKD) who had complained of chronic abdominal distension due to prominent ascites presented with sudden dyspnea. Chest radiography showed massive right pleural effusion that shifted the mediastinum. Peritoneal scintigraphy using 99mTc-macroaggregated albumin revealed pleuroperitoneal communication (PPC). As her hydrothorax was refractory and frequent thoracentesis did not improve her respiratory distress, thoracoscopic surgery was performed for repair of the diaphragm defect. Continuous ambulatory peritoneal dialysis (CAPD) was started soon after surgery because her renal function was progressively worsening, and there was no recurrence of hydrothorax. The chronic abdominal distension resolved as her ascites decreased. In addition, peritoneal protein loss decreased after initiation of peritoneal dialysis (PD). PPC is an uncommon but serious complication of PD, and PD patients with PPC are often forced to discontinue PD. To our knowledge, no report has presented successful PD induction in a patient with evident PPC. We believe that further accumulation of such cases will expand the treatment options for CKD.â©.
Asunto(s)
Ascitis/terapia , Diafragma/cirugía , Hidrotórax/terapia , Fallo Renal Crónico/terapia , Cirrosis Hepática , Diálisis Peritoneal Ambulatoria Continua/métodos , Anciano , Ascitis/diagnóstico por imagen , Ascitis/etiología , Progresión de la Enfermedad , Femenino , Humanos , Hidrotórax/diagnóstico por imagen , Hidrotórax/etiología , Fallo Renal Crónico/complicaciones , Cirrosis Hepática/complicaciones , Recurrencia , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapia , Albúmina Sérica , Agregado de Albúmina Marcado con Tecnecio Tc 99m , Toracoscopía , Compuestos de EstañoRESUMEN
BACKGROUND: Amyloid A amyloidosis is one of the most common forms of amyloidosis. It is secondary to rheumatoid arthritis, which is difficult to manage and has a poor prognosis. We present a patient with rheumatoid arthritis and amyloid A amyloidosis who was treated with tocilizumab, a humanized monoclonal antibody against interleukin 6 receptor, resulting in improvement in both proteinuria and gastrointestinal symptoms; however, amyloid deposition remained. CASE PRESENTATION: A 67-year-old woman who had previously been treated for rheumatoid arthritis presented with abdominal pain and diarrhea. Right renal cell carcinoma was found, and amyloid A amyloidosis was diagnosed concomitantly based on colon biopsy. The renal cell carcinoma was resected, and the non-cancerous part of the renal tissue also showed amyloid A deposition. Following surgery, protein levels in the urine increased to the nephrotic range, and administration of tocilizumab was initiated, which resulted in resolution of the proteinuria. The patient's gastrointestinal symptoms were also alleviated. However, repeat colon biopsy showed amyloid deposition. CONCLUSIONS: This case of amyloid A amyloidosis suggests that amyloid deposition indicates only structural change of the affected tissue, and that it is not amyloid deposition per se that causes the clinical symptoms of amyloidosis.
Asunto(s)
Amiloidosis/diagnóstico , Amiloidosis/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Colon/patología , Riñón/patología , Proteína Amiloide A Sérica , Anciano , Femenino , Humanos , Resultado del TratamientoRESUMEN
Hypertension is well-known to often coexist with diabetes mellitus (DM) in humans. Treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors has been shown to decrease both the blood glucose and the blood pressure (BP) in such patients. Some reports show that SGLT2 inhibitors improve the BP by decreasing the activities of the sympathetic nervous system. Therefore, we hypothesized that SGLT2 inhibitors might alleviate hypertension via attenuating sympathetic nervous activity. Combined SGLT2/SGLT1 inhibitor therapy is also reported as being rather effective for decreasing the BP. In this study, we examined the effects of SGLT2 and SGLT1 inhibitors on the bulbospinal neurons of the rostral ventrolateral medulla (RVLM). To investigate whether bulbospinal RVLM neurons are sensitive to SGLT2 and SGLT1 inhibitors, we examined the changes in the neuronal membrane potentials (MPs) of these neurons using the whole-cell patch-clamp technique during superfusion of the cells with the SGLT2 and SGLT1 inhibitors. A brainstem-spinal cord preparation was used for the experiments. Our results showed that superfusion of the RVLM neurons with SGLT2 and SGLT1 inhibitor solutions induced hyperpolarization of the neurons. Histological examination revealed the presence of SGLT2s and SGLT1s in the RVLM neurons, and also colocalization of SGLT2s with SGLT1s. These results suggest the involvement of SGLT2s and SGLT1s in regulating the activities of the RVLM neurons, so that SGLT2 and SGLT1 inhibitors may inactivate the RVLM neurons hyperpolarized by empagliflozin. SGLT2 and SGLT1 inhibitors suppressed the activities of the bulbospinal RVLM neurons in the brainstem-spinal preparations, suggesting the possibilities of lowering BP by decreasing the sympathetic nerve activities. RVLM, rostral ventrolateral medulla. IML, intralateral cell column. aCSF, artificial cerebrospinal fluid.
Asunto(s)
Hipertensión , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Ratas , Animales , Ratas Wistar , Transportador 2 de Sodio-Glucosa , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Neuronas , Bulbo Raquídeo , Sistema Nervioso SimpáticoRESUMEN
Introduction: Antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN) is characterized by pauci-immune crescentic GN. Myeloperoxidase ANCA-associated GN (MPO-ANCA GN) with membranous nephropathy (MN), where bright granular capillary MPO and IgG staining along the glomerular basement membrane (GBM) is present, has been reported; however, its clinicopathological features remain unclear. Methods: We investigated 7 MPO-ANCA GN with MN and 11 control cases (6 MPO-ANCA GN and 5 primary MN cases). Proteomics of laser microdissected glomeruli followed by immunohistochemical analysis was performed to identify causal antigens in MPO-ANCA GN with MN. We described the clinicopathological features of MPO-associated MN compared with those of MPO-ANCA GN and primary MN. Results: We detected proteomic MPO and granular capillary MPO deposits in all MPO-ANCA GN with MN cases. Confocal microscopy revealed MPO and IgG colocalization along the GBM. MPO-associated MN clinicopathological features include greater proteinuria, a higher fibrous crescent rate, and a lower MPO-ANCA titer than MPO-ANCA GN. The estimated glomerular filtration rate (eGFR) and urinary protein excretion were lower in MPO-associated MN than in primary MN. Conclusion: MPO-associated MN, a unique type of secondary MN where MPO serves as the causal antigen, is a subset of MPO-ANCA GN with MN. Prolonged periods of MPO-ANCA GN and a low MPO-ANCA titer might be related to MPO-associated MN development.
RESUMEN
Lecithin-cholesterol acyltransferase (LCAT) plays a significant role in the progression from premature to mature high-density lipoprotein (HDL) in circulation. Consequently, primary or secondary LCAT deletion or reduction naturally results in low serum HDL cholesterol levels. Recently, rare cases of acquired HDL deficiency with LCAT autoantibodies have been reported, mainly from Japan, where LCAT autoantibodies of immunoglobulin G (IgG) caused the HDL deficiency. Here to our knowledge, we report for the first time two cases of acquired HDL deficiency caused by IgG4 linked LCAT autoantibodies with or without a high serum IgG4 level. Furthermore, these cases can extend to a new concept of "IgG4 autoimmune disease" from the viewpoint of verifying the serum autoantibody and/or renal histopathology.
Asunto(s)
Deficiencia de la Lecitina Colesterol Aciltransferasa , Lecitinas , Humanos , Esterol O-Aciltransferasa , Autoanticuerpos , Fosfatidilcolina-Esterol O-Aciltransferasa , Lipoproteínas HDL , Inmunoglobulina G , HDL-ColesterolRESUMEN
The 2009 pandemic H1N1 influenza A virus spread quickly worldwide in 2009. Since most of the fatal cases were reported in developing countries, rapid and accurate diagnosis methods that are usable in poorly equipped laboratories are necessary. In this study, a mobile detection system for the 2009 H1N1 influenza A virus was developed using a reverse-transcriptase loop-mediated isothermal amplification (RT-LAMP) kit with a disposable pocket-warmer as a heating device (designated as pwRT-LAMP). The pwRT-LAMP can detect as few as 100 copies of the virus--which is nearly as sensitive as real-time reverse-transcription polymerase chain reaction (RT-PCR)--and does not cross-react with RNA of seasonal influenza viruses. To evaluate the usefulness of the pwRT-LAMP system, nasal swab samples were collected from 56 patients with flu-like symptoms and were tested. Real-time RT-PCR confirmed that the 2009 H1N1 influenza A virus was present in 27 of the 56 samples. Of these 27 positive samples, QuickVue Influenza A+B immunochromatography detected the virus in only 11 samples (11/27; 40.7%), whereas the pwRT-LAMP system detected the virus in 26 of the 56 samples (26/27 of the positive samples; 96.3%). These findings indicate that the mobile pwRT-LAMP system is an accurate diagnostic system for the 2009 H1N1 influenza A virus, and has great potential utility in diagnosing future influenza pandemics.
Asunto(s)
Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/diagnóstico , Gripe Humana/virología , Técnicas de Amplificación de Ácido Nucleico/métodos , Sistemas de Atención de Punto , Virología/métodos , Adulto , Femenino , Humanos , Subtipo H1N1 del Virus de la Influenza A/genética , Masculino , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
Hypertension often occurs in patients with chronic kidney disease (CKD). Considering the decrease in serum Klotho and increase in serum FGF23 levels in such patients, decreased Klotho and increased FGF23 levels were thought to be associated with hypertension. Presympathetic neurons at the rostral ventrolateral medulla (RVLM) contribute to sympathetic activity and regulation of blood pressure. Therefore, we hypothesized that Klotho would reduce the activities of RVLM neurons and FGF23 would stimulate them. Accordingly, this study examined the effects of Klotho and FGF23 on bulbospinal neurons in the RVLM. We used a brainstem-spinal cord preparation to record from RVLM presympathetic neurons and to evaluate the effects of Klotho and FGF23 on firing rate and membrane potentials of these neurons. Our results showed that Klotho-induced RVLM neuron hyperpolarization, while ouabain, a Na+/K+-ATPase inhibitor, suppressed the effects of Klotho on such neurons. Moreover, FGF23 induced RVLM neuron depolarization, while SU5402, an FGF23 receptor (FGFR1) antagonist, induced RVLM neuron hyperpolarization. Histological examinations revealed that Klotho, Na+/K+-ATPase, FGF23, and FGFR1 were present in RVLM neurons and that Klotho was localized in the same neurons as FGFR1. These results suggest that Klotho and FG23 regulate the activity of RVLM neurons. Klotho may reduce the activity of RVLM neurons via stimulating Na+/K+-ATPase on those neurons while FGF23 may activate those neurons via FGFR1.
Asunto(s)
Factores de Crecimiento de Fibroblastos/farmacología , Glucuronidasa/farmacología , Bulbo Raquídeo/efectos de los fármacos , Neuronas/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Animales Recién Nacidos , Hipertensión/fisiopatología , Proteínas Klotho , Potenciales de la Membrana/efectos de los fármacos , Neuronas/fisiología , Ratas Wistar , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiopatología , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
A 76-year-old woman suddenly developed anasarca and a fever, and an examination revealed thrombocytopenia, reticulin fibrosis, and acute kidney injury, yielding the diagnosis of thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly (TAFRO) syndrome. Renal replacement therapy and steroid treatment were soon started. Her proteinuria was minor at first; however, once the kidney function improved, nephrotic syndrome occurred. A kidney biopsy showed membranoproliferative glomerulonephritis-like glomerulopathy with massive macrophage infiltration. Although kidney dysfunction is often observed in TAFRO syndrome patients, its detailed mechanism is unclear. This case suggests that TAFRO syndrome involves both acute kidney injury with minor proteinuria and nephrotic syndrome, and these disorders can develop serially in the same patient.
Asunto(s)
Lesión Renal Aguda/etiología , Edema/diagnóstico , Fiebre/diagnóstico , Síndrome Nefrótico/etiología , Trombocitopenia/diagnóstico , Anciano , Edema/complicaciones , Femenino , Fiebre/complicaciones , Fibrosis/complicaciones , Fibrosis/diagnóstico , Glomerulonefritis Membranoproliferativa/etiología , Glomerulonefritis Membranoproliferativa/patología , Humanos , Riñón/patología , Proteinuria/etiología , SíndromeRESUMEN
Fasudil, a Rho-kinase inhibitor, may improve insulin signaling. However, its long-term effect on metabolic abnormalities and its preventive effect on diabetic nephropathy are still unknown. We assessed these effects of fasudil in insulin-resistant diabetic rats, comparing them with those of an angiotensin II receptor blocker, olmesartan. Male Otsuka Long-Evans Tokushima fatty (OLETF) and Long-Evans Tokushima Otsuka, non-diabetic control, rats at 15 weeks of age were used. OLETF rats were randomized to receive a low or a high dose of fasudil or olmesartan for 25 weeks. To examine the therapeutic effects after the development of diabetes, OLETF rats at 30 weeks of age were given fasudil for 10 weeks. Administration of high-dose fasudil completely suppressed the development of diabetes, obesity, and dyslipidemia and increased serum adiponectin levels in OLETF rats. High-dose olmesartan also decreased hemoglobin A1c and increased serum adiponectin. There was a significant correlation between hemoglobin A1c and serum adiponectin or free fatty acid levels. The treatment with high-dose fasudil ameliorated proteinuria, glomerulosclerosis, renal interstitial fibrosis, and macrophage infiltration in OLETF rats. Olmesartan, even at the low dose, suppressed renal complications. The treatment with fasudil after the development of diabetes improved the metabolic abnormalities in OLETF rats, but could not suppress the progression of nephropathy. We conclude that the long-term treatment with fasudil prevents the development of diabetes, at least in part, by improving adipocyte differentiation in insulin-resistant diabetic rats. Early use of fasudil may prevent diabetic nephropathy.
Asunto(s)
1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Diabetes Mellitus Tipo 1/prevención & control , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/uso terapéutico , Animales , Glucemia/metabolismo , Proteínas Portadoras/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/prevención & control , Inhibidores Enzimáticos/uso terapéutico , Hemoglobina Glucada/metabolismo , Imidazoles/farmacología , Riñón/química , Riñón/patología , Metabolismo de los Lípidos , Masculino , Fosfoproteínas Fosfatasas/metabolismo , Proteína Fosfatasa 1 , Ratas , Ratas Endogámicas OLETF , Factor Rho/metabolismo , Transducción de Señal/fisiología , Tetrazoles/farmacología , Quinasas Asociadas a rhoRESUMEN
The mechanisms of hypertensive nephrosclerosis are not fully understood. In experimental models of the disease, inflammatory reactions such as macrophage infiltration play an important role. In human hypertensive nephrosclerosis, however, there have been few studies examining the role of inflammation histologically. We investigated whether the number of infiltrating macrophages was increased in human hypertensive nephrosclerosis, and evaluated the effects of a blockade of the renin-angiotensin system on clinical and histological findings. We examined macrophage infiltration using immunohistochemistry in renal biopsy specimens obtained from 16 patients with hypertensive nephrosclerosis, 5 patients with IgA nephropathy, 5 patients with membranous nephropathy, and 5 patients with minimal change nephrotic syndrome. The number of infiltrating macrophages in glomeruli was significantly larger in the patients with hypertensive nephrosclerosis than in those with minimal change nephrotic syndrome. The patients with hypertensive nephrosclerosis were divided into groups based on their use of antihypertensive agents at the time of renal biopsy. We investigated the effects of antihypertensive agents on clinical findings, macrophage infiltration, and monocyte chemoattractant protein-1 expression. There was no difference in clinical findings between the hypertensive groups. The numbers of infiltrating macrophages and monocyte chemoattractant protein-1-positive cells in glomeruli were significantly smaller in patients treated with an angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor blocker, whereas calcium channel blockers had no influence on histological findings. In conclusion, inflammation is involved in the progression of human hypertensive nephrosclerosis and the inflammatory process is inhibited by blocking the renin-angiotensin system.
Asunto(s)
Movimiento Celular/fisiología , Hipertensión/complicaciones , Macrófagos/patología , Nefroesclerosis/etiología , Nefroesclerosis/patología , Sistema Renina-Angiotensina/fisiología , Adolescente , Adulto , Anciano , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Biopsia , Movimiento Celular/efectos de los fármacos , Quimiocina CCL2/metabolismo , Glomerulonefritis por IGA/etiología , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/fisiopatología , Glomerulonefritis Membranosa/etiología , Glomerulonefritis Membranosa/patología , Glomerulonefritis Membranosa/fisiopatología , Humanos , Hipertensión/fisiopatología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Glomérulos Renales/fisiopatología , Macrófagos/efectos de los fármacos , Persona de Mediana Edad , Nefroesclerosis/fisiopatología , Nefrosis Lipoidea/etiología , Nefrosis Lipoidea/patología , Nefrosis Lipoidea/fisiopatología , Sistema Renina-Angiotensina/efectos de los fármacos , Estudios RetrospectivosRESUMEN
BACKGROUND: Transglutaminase (Tg)-2 is shown to be related to renal fibrosis. However, its roles in human kidney disease have not been fully studied. METHODS: Using immunohistochemistry, we examined Tg-2 expression in renal biopsy specimens from 22 patients with IgA nephropathy (IgAN) and correlated the intensity of Tg-2 staining with clinical and histopathological parameters. We compared the distribution and intensity of Tg-2 staining with those of transforming growth factor (TGF)-beta staining. RESULTS: In normal human kidneys, Tg-2 staining was not significant. In IgAN kidneys, glomerular Tg-2 staining correlated with serum creatinine (S-Cr), creatinine clearance (Ccr), urinary protein excretion, glomerular sclerosis, and mesangial cell proliferation. Tubulointerstitial Tg-2 correlated with S-Cr, Ccr, N-acetyl-beta-glucosaminidase, urinary beta(2)-microglobulin, and tubulointerstitial injuries. Tg-2 staining in the vicinity of vascular poles of glomeruli preceded the development of mesangial lesions, and was more remarkable in cases with renal impairment. The distribution and intensity of Tg-2 staining were not consistent with those of TGF-beta staining. In glomerular crescents, Tg-2 staining was remarkable. CONCLUSION: The present study showed a correlation between Tg-2 expression and renal function and pathological changes. Tg-2 expression in the vicinity of vascular poles was notable because that may be an initial marker of glomerular injury.