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1.
Intern Med ; 57(14): 2035-2039, 2018 Jul 15.
Article in English | MEDLINE | ID: mdl-29491316

ABSTRACT

Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of early onset diabetes. The hepatocyte nuclear factor-1-beta (HNF1B) gene is responsible for MODY type 5 (MODY5) with distinctive clinical features, including pancreatic atrophy and renal disease. We herein report a Japanese case of young-onset diabetes with typical phenotypes of MODY5 and a novel heterozygous missense mutation (p.L145Q) in the HNF1B gene. The mutation was located in the Pit-Oct-Unc (POU)-specific domain, and the amino acid residue L145 was highly conserved among species. It is strongly suggested that this mutation explains the phenotypes of MODY5.


Subject(s)
Diabetes Mellitus, Type 2/genetics , Hepatocyte Nuclear Factor 1-beta/genetics , Central Nervous System Diseases , Child , Dental Enamel/abnormalities , Humans , Kidney Diseases, Cystic , Male , Mutation , Mutation, Missense , Phenotype
2.
Intern Med ; 56(11): 1375-1381, 2017.
Article in English | MEDLINE | ID: mdl-28566601

ABSTRACT

A 53-year-old woman developed end-stage renal failure during a 15-year clinical course of primary hyperparathyroidism and was referred to our hospital for evaluation of suspected multiple endocrine neoplasia type 1 (MEN1). Genetic testing revealed a novel deletion mutation at codon 467 in exon 10 of the MEN1 gene. Systemic and selective arterial calcium injection (SACI) testing revealed hyperglucagonemia and hypergastrinemia with positive gastrin responses. A pathological examination revealed glucagonoma and a lymph node gastrinoma. The findings in this case indicate the importance of early diagnosis of MEN1 and demonstrate the utility of systemic and SACI testing in renal failure cases.


Subject(s)
Multiple Endocrine Neoplasia Type 1/diagnosis , Multiple Endocrine Neoplasia Type 1/physiopathology , Diagnosis, Differential , Female , Gastrinoma/diagnosis , Glucagonoma/diagnosis , Humans , Kidney Failure, Chronic/diagnosis , Lymph Nodes/pathology , Middle Aged , Multiple Endocrine Neoplasia Type 1/genetics , Pancreatic Neoplasms/diagnosis , Proto-Oncogene Proteins , Renal Insufficiency, Chronic/genetics
3.
Intern Med ; 56(7): 797-803, 2017.
Article in English | MEDLINE | ID: mdl-28381746

ABSTRACT

We report a rare case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) associated with amyotrophic lateral sclerosis (ALS). A 69-year-old man was admitted to our hospital with sustained hyponatremia. Hyposmolality with elevated urinary osmolality and sodium excretion was observed, which indicated SIADH. The treatment for SIADH was challenging; the patient developed carbon dioxide narcosis, which led to the diagnosis of ALS. After the initiation of noninvasive positive-pressure ventilation, the patient's serum sodium concentration normalized and became stable. Thus, ALS should be recognized as a possible cause of SIADH in the clinical setting.


Subject(s)
Amyotrophic Lateral Sclerosis/complications , Carbon Dioxide/adverse effects , Inappropriate ADH Syndrome/complications , Inert Gas Narcosis/complications , Aged , Humans , Hyponatremia/complications , Male , Osmolar Concentration
4.
Tohoku J Exp Med ; 239(2): 89-94, 2016 06.
Article in English | MEDLINE | ID: mdl-27212224

ABSTRACT

Mitochondrial diabetes mellitus is a subtype of diabetes linked to mutations in mitochondrial DNA. In patients with mitochondrial diabetes mellitus, the effect of glycemic control on the serum concentrations of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) has not been evaluated. FGF21 and GDF15 have been reported to be useful biomarkers for the diagnosis and severity assessment of mitochondrial diseases like mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Recent studies have shown FGF21 acts in an endocrine fashion to regulate glucose and lipid metabolism in type 2 diabetes mellitus, while the exact biological functions of GDF15 remain unknown. Although mitochondrial diabetes mellitus is commonly found in cases with mitochondrial diseases, the comparison of FGF21 and GDF15 levels between those with and without diabetes has not been performed. Here, we report a 24-year-old woman with mitochondrial diabetes mellitus, who showed a high level of serum FGF21, but not serum GDF15, at diagnosis. In our case, liraglutide, a glucagon-like peptide-1 receptor agonist, added to insulin glargine was effective for her glycemic control and showed no adverse effects, including gastrointestinal symptoms and hypoglycemia, during a 14-week observation. The successful glycemic control caused a decrease in the FGF21 level, without affecting the GDF15 level. Thus, we should consider patients' glycemic control levels in using FGF21 values for the diagnosis of mitochondrial diseases. In addition, sustained GDF15 levels during glycemic treatment in our case suggest the usefulness of GDF15 as a marker for clinical severity of muscle-manifested mitochondrial diseases.


Subject(s)
Diabetes Mellitus, Type 2/blood , Fibroblast Growth Factors/blood , Growth Differentiation Factor 15/blood , Hyperglycemia/blood , Mitochondrial Diseases/blood , Diabetes Mellitus, Type 2/complications , Female , Humans , Hyperglycemia/complications , Mitochondrial Diseases/complications , Patient Admission , Patient Discharge , Young Adult
5.
Tohoku J Exp Med ; 238(4): 311-6, 2016 04.
Article in English | MEDLINE | ID: mdl-27063563

ABSTRACT

Approximately 80% of patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) carry the A3243G mutation in the mitochondrial tRNALeu (UUR) gene. Conversely, this mutation has also been identified as one of the most prevalent genetic abnormalities in patients with diabetes mellitus. Mitochondrial diabetes mellitus complicated with MELAS is relatively common, and 12.5% of patients with the A3243G mutation develop MELAS after being diagnosed with diabetes mellitus. However, the clinical impact of diabetes mellitus in MELAS patients remains unclear. Therefore, we retrospectively studied 14 Japanese MELAS patients with the A3243G mutation: three men and eleven women, with the mean age of 48.0 (± 15.4) years. Eight patients had been diagnosed with diabetes mellitus prior to the diagnosis of mitochondrial disease, and all of them were treated with insulin. The other six included four patients with concurrent diagnosis of diabetes and mitochondrial disease, one patient diagnosed with diabetes after the diagnosis of mitochondrial disease, and one patient without developing diabetes currently. We thus compared the patients' characteristics between those with and without early onset of diabetes mellitus. Cognitive decline (75.0% vs. 0%; p = 0.03) and poor glycemic control with severe hypoglycemic events (75.0% vs. 16.7%; p = 0.05) were more common in MELAS patients with a prior diagnosis of diabetes than in those without the prior diagnosis of diabetes. Our data suggest that the latent progress of cognitive decline is accelerated because of early onset of diabetes mellitus in MELAS patients.


Subject(s)
Cognition Disorders/etiology , Diabetes Complications , Diabetes Mellitus , MELAS Syndrome/complications , Age of Onset , Female , Humans , Male , Middle Aged , Mutation , Retrospective Studies
6.
Intern Med ; 54(19): 2475-81, 2015.
Article in English | MEDLINE | ID: mdl-26424307

ABSTRACT

A 35-year-old obese diabetic man presented with recurrent primary hyperparathyroidism during a three-year outpatient follow-up. He was clinically diagnosed with multiple endocrine neoplasia type 1 (MEN1) due to the presence of a pituitary adenoma and multiple glucagonomas. The glucagonomas may have affected his glycemic control. However, he did not demonstrate weight loss, suggesting that the patient's obesity could have obscured the early diagnosis of a glucagonoma. Genetic testing revealed a novel missense mutation at codon 561 in exon 10, resulting in an amino acid substitution from methionine to arginine (M561R) in the MEN1 gene. This mutation appeared to be responsible for the MEN1 pathogenicity.


Subject(s)
Glucagonoma/diagnosis , Hyperparathyroidism, Primary/diagnosis , Multiple Endocrine Neoplasia Type 1/diagnosis , Mutation, Missense/genetics , Pancreatic Neoplasms/diagnosis , Adult , Amino Acid Substitution , DNA Mutational Analysis , Diabetes Mellitus, Type 2 , Genetic Testing , Glucagonoma/genetics , Glucagonoma/surgery , Humans , Hyperparathyroidism, Primary/etiology , Hyperparathyroidism, Primary/genetics , Male , Multiple Endocrine Neoplasia Type 1/genetics , Multiple Endocrine Neoplasia Type 1/surgery , Obesity/complications , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/surgery , Proto-Oncogene Proteins
7.
Intern Med ; 54(7): 807-12, 2015.
Article in English | MEDLINE | ID: mdl-25832947

ABSTRACT

A 55-year-old man presented with a rapidly enlarging thyroid. He had been diagnosed with lung adenocarcinoma nine months earlier. Computed tomography (CT) and ultrasound (US) detected reticular cord-like structures, but no nodules, in the thyroid. A fine-needle aspiration biopsy (FNAB) of the thyroid revealed thyroglobulin-negative adenocarcinoma cells, thus establishing the diagnosis of diffuse thyroid metastases of lung cancer. Moreover, the fluid demonstrated milky chyliform effusion. This case suggests that the presence of reticular cord-like structures on US and CT may be a key imaging finding for the clinical diagnosis of diffuse thyroid metastases and that chyliform effusion may contribute to rapid goiter formation.


Subject(s)
Adenocarcinoma/pathology , Biopsy, Fine-Needle , Goiter/pathology , Lung Neoplasms/pathology , Thyroglobulin/metabolism , Thyroid Neoplasms/secondary , Adenocarcinoma/secondary , Adenocarcinoma of Lung , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Fatal Outcome , Humans , Lung Neoplasms/secondary , Male , Middle Aged , Radiopharmaceuticals , Sensitivity and Specificity , Tomography, X-Ray Computed , Ultrasonography, Interventional
8.
Tohoku J Exp Med ; 235(4): 255-60, 2015 04.
Article in English | MEDLINE | ID: mdl-25810423

ABSTRACT

The combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor and a long-acting insulin analogue is widely used in clinical practice. However, some patients fail to achieve lower postprandial hyperglycemia. Mitiglinide, a short-acting insulinotropic sulfonylurea receptor ligand, is effective for postprandial hyperglycemia. Recently, it has been reported that the combination therapy of mitiglinide with a DPP-4 inhibitor could improve glycemic control. However, the efficacy of those under long-acting insulin analogue therapy remains to be investigated. Thus, we conducted a prospective single-center study of eight Japanese patients with type 2 diabetes mellitus receiving mitiglinide added to the combination therapy of sitagliptin and insulin glargine, and evaluated its efficacy and safety by continuous glucose monitoring (CGM). Participants' (four men and four women) mean age was 70.3 ± 10.6 years. Their mean body mass index, HbA1c level, and urinary C-peptide level were 22.0 ± 2.8 kg/m(2), 9.2 ± 1.2%, and 50.0 ± 31.4 µg/day, respectively. CGM showed that as compared with the combination of only sitagliptin and insulin glargine, mitiglinide in combination with sitagliptin and insulin glargine significantly reduced glycemic fluctuation indices, total area for the range of 24-h glycemic fluctuations (p = 0.04), mean amplitude of glycemic excursions (p = 0.03), and the proportion of time in hyperglycemia (p = 0.02) without significant difference in the proportion of time in hypoglycemia (p = 0.18). Hence, we have demonstrated the efficacy and safety of the add-on treatment with mitiglinide in type 2 diabetic patients, receiving the combination therapy of sitagliptin and insulin glargine.


Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Hyperglycemia/complications , Hyperglycemia/drug therapy , Insulin Glargine/therapeutic use , Isoindoles/therapeutic use , Sitagliptin Phosphate/therapeutic use , Aged , Blood Glucose/analysis , Diabetes Mellitus, Type 2/blood , Drug Therapy, Combination , Fasting/blood , Female , Humans , Hyperglycemia/blood , Male , Monitoring, Physiologic
9.
Intern Med ; 53(19): 2227-32, 2014.
Article in English | MEDLINE | ID: mdl-25274235

ABSTRACT

We herein describe two patients with a prolonged disturbance of consciousness due to severe hypophosphatemia. Case one presented with pneumococcal infection and acute exacerbation of chronic obstructive pulmonary disease and asthma. Case two presented with diabetic foot infections and diabetic ketoacidosis. Both patients responded to initial therapy for their primary diseases, but consciousness became worse in both cases. Their test results for impaired consciousness revealed severe hypophosphatemia; therefore, phosphate replacement therapy was administered, thus resulting in complete alertness. These cases demonstrate that we should consider the possibility of hypophosphatemia in critically ill patients with an altered consciousness.


Subject(s)
Consciousness , Hypophosphatemia/complications , Nutritional Support/methods , Phosphorus, Dietary/administration & dosage , Unconsciousness/etiology , Aged , Asthma/complications , Diabetic Ketoacidosis/complications , Female , Follow-Up Studies , Humans , Hypophosphatemia/blood , Hypophosphatemia/drug therapy , Middle Aged , Phosphates/blood , Pulmonary Disease, Chronic Obstructive/complications , Severity of Illness Index , Unconsciousness/drug therapy , Unconsciousness/physiopathology
10.
Endocr J ; 61(8): 773-9, 2014.
Article in English | MEDLINE | ID: mdl-24849384

ABSTRACT

Central diabetes insipidus (CDI) is a rare disease characterized by polyuria and polydipsia. Patients with CDI have been successfully treated with desmopressin administered either by intranasal instillation or oral tablets. Recently, a desmopressin orally disintegrating tablet (ODT) was approved as the first oral desmopressin tablet for CDI treatment in Japan. We conducted a retrospective single-center study of 15 Japanese CDI patients treated with desmopressin ODT therapy, which aimed to evaluate the efficacy and safety of switching to desmopressin ODT and to analyze the clinical factors that affect the desmopressin ODT dose in Japanese patients. The daily mean dose of desmopressin ODT was 104 ± 46.30 µg and the mean ratio of oral to nasal desmopressin dose was 17.0 ± 7.6, both of which are considerably smaller than those of previous dose-titration study. Moreover, the nasal spray group needed significantly smaller ratios of nasal to oral desmopressin than the nasal drop group (11.7 ± 6.5 vs 21.0 ± 5.5, p = 0.02). The ratio of oral to nasal desmopressin dose had a significant inverse correlation with the required nasal desmopressin dose. Multiple regression analysis demonstrated the ratios of nasal to oral desmopressin dose depended on intranasal formulations. In conclusion, desmopressin ODT was safe and effective in the treatment of Japanese adult CDI patients. When switching to ODT, we should care about the possibility that patients require smaller ODT doses than what was initially expected based on previously published data and also nasal formulations in terms of their differences of expected switching ratio.


Subject(s)
Antidiuretic Agents/administration & dosage , Deamino Arginine Vasopressin/administration & dosage , Diabetes Insipidus, Neurogenic/drug therapy , Drug Substitution , Administration, Intranasal , Administration, Oral , Adult , Aged , Aged, 80 and over , Female , Humans , Japan/epidemiology , Male , Middle Aged , Retrospective Studies , Tablets
11.
Intern Med ; 53(7): 743-7, 2014.
Article in English | MEDLINE | ID: mdl-24694489

ABSTRACT

We herein describe the case of a woman with pseudohypoparathyroidism (PHP) type II. She had a history of subtotal thyroidectomy against Graves' disease without levothyroxine supplementation and presented with stiffness, numbness and muscle cramps. Her surgical history suggested the possibility of secondary hypoparathyroidism; however, the serum intact parathyroid hormone level and results of a Ellsworth-Howard test led to the diagnosis of PHP type II. In the present case, making the differential diagnosis was challenging because two distinct disorders, such as PHP and secondary hypoparathyroidism, may exist simultaneously. This case demonstrates the need to consider the possibility of PHP type II in patients exhibiting hypocalcemia.


Subject(s)
Graves Disease/surgery , Parathyroid Hormone/blood , Pseudohypoparathyroidism/etiology , Thyroidectomy , Aged , Diagnosis, Differential , Female , Humans , Pseudohypoparathyroidism/blood , Pseudohypoparathyroidism/diagnosis
12.
Intern Med ; 52(1): 89-95, 2013.
Article in English | MEDLINE | ID: mdl-23291680

ABSTRACT

Glucocorticoid-induced hyperglycemia is common in patients with or without known diabetes mellitus. Exenatide, a glucagon-like peptide-1 receptor agonist, improves glycemic control without causing weight gain or hypoglycemia and is currently widely used in patients with type 2 diabetes mellitus. We herein report four cases of patients with type 2 diabetes with worsened glycemic control due to glucocorticoids who were successfully treated with exenatide administration.


Subject(s)
Blood Glucose/drug effects , Diabetes Mellitus, Type 2/drug therapy , Glucocorticoids/adverse effects , Hyperglycemia/chemically induced , Hypoglycemic Agents/therapeutic use , Peptides/therapeutic use , Venoms/therapeutic use , Adult , Aged , Aged, 80 and over , Blood Glucose/analysis , Diabetes Mellitus, Type 2/diagnosis , Dose-Response Relationship, Drug , Drug Administration Schedule , Exenatide , Female , Follow-Up Studies , Glucocorticoids/therapeutic use , Humans , Hyperglycemia/drug therapy , Hyperglycemia/physiopathology , Injections, Subcutaneous , Insulin/therapeutic use , Male , Middle Aged , Risk Assessment , Sampling Studies , Treatment Outcome
13.
J Diabetes Investig ; 4(1): 69-77, 2013 Jan 29.
Article in English | MEDLINE | ID: mdl-24843633

ABSTRACT

AIMS/INTRODUCTION: Liraglutide, a glucagon-like peptide-1 receptor agonist, is expected to provide a new treatment option for diabetes. However, the suitable timing of liraglutide administration in type 2 diabetic patients has not yet been clarified. MATERIALS AND METHODS: We reviewed type 2 diabetic patients (n = 155) who visited the Osaka Red Cross Hospital for glycemic control, with administration of liraglutide at a dose of 0.6 mg (average glycated hemoglobin [HbA1c] level, 8.7 ± 0.1%). The effect of liraglutide based on the pretreatment status was compared. We also analyzed the background factors of both a successful and failed group of patients who switched to liraglutide from insulin. RESULTS: An improvement in blood glucose levels was confirmed in 122 of 155 patients. During the 4-month observation period, the improvement in HbA1c levels was significantly greater in the group of drug-naïve/previous oral hypoglycemic agent (9.1 ± 0.2 to 7.2 ± 0.2%) than that in the group switching from insulin (8.6 ± 0.2 to 7.8 ± 0.2%). In addition, C-peptide immunoreactivity levels (fasting > 2.2 ng/mL; delta >1.6 ng/mL; urine > 70 µg/day), younger age and a smaller number of insulin units used per day were considered important when deciding on switching to liraglutide from insulin. CONCLUSIONS: Liraglutide was more effective in patients who had not been treated previously or received oral hypoglycemic agents than in patients switching from insulin. With respect to switching to liraglutide from insulin, the most important factors to be considered were C-peptide immunoreactivity levels, age, and the number of insulin units used per day.

14.
Intern Med ; 51(18): 2591-5, 2012.
Article in English | MEDLINE | ID: mdl-22989832

ABSTRACT

Acid-base imbalances and electrolyte disorders induced by proton pump inhibitors (PPIs) are extremely rare. However, under certain conditions, PPIs may cause metabolic acidosis or hypokalemia, probably due to an inhibitory action on the proton pump that contributes to H(+) and K(+) homeostasis in the kidney. We herein present a case of marked hypokalemia accompanied by distal renal tubular acidosis in which a PPI appeared to contribute to the pathophysiology of metabolic acidosis.


Subject(s)
Acidosis, Renal Tubular/chemically induced , Gastroesophageal Reflux/drug therapy , Proton Pump Inhibitors/adverse effects , Proton Pump Inhibitors/therapeutic use , Acidosis, Renal Tubular/diagnosis , Female , H(+)-K(+)-Exchanging ATPase/drug effects , Homeostasis/drug effects , Humans , Hydrogen/metabolism , Hypokalemia/chemically induced , Hypokalemia/diagnosis , Kidney/metabolism , Middle Aged , Potassium/metabolism , Proton Pump Inhibitors/pharmacology
15.
Diabetes Res Clin Pract ; 96(3): 326-30, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22306059

ABSTRACT

Diabetic ketoacidosis (DKA) is an acute, life-threatening complication of diabetes mellitus and is caused by insulin insufficiency. Hypothermia is defined as a core temperature of less than 35°C and is sometimes accompanied by DKA. We report two patients with diabetes who were admitted for DKA accompanied by hypothermia.


Subject(s)
Diabetes Mellitus, Type 1/blood , Diabetic Ketoacidosis/blood , Diabetic Ketoacidosis/complications , Hypothermia/blood , Hypothermia/complications , Thinness/blood , Aged , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/physiopathology , Diabetic Ketoacidosis/drug therapy , Diabetic Ketoacidosis/physiopathology , Humans , Hypothermia/drug therapy , Hypothermia/physiopathology , Male , Rewarming , Risk Factors , Treatment Outcome
16.
Endocr J ; 53(3): 393-9, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16717394

ABSTRACT

Hepatitis C-Associated Osteosclerosis (HCAO) is characterized by a marked increase in bone mass with deep bone pain. Since 1992, eleven cases of HCAO have been reported. This report describes an elderly Japanese man with HCAO, whose clinical course we followed for 3 years. A 68-year-old man developed pain in both pretibial regions in June 2000, and he had frequent episodic loss of muscular strength in his hands. He had recieved blood transfusion for a bleeding ulcer 43 years before and was seropositive for hepatitis C virus. His serum alkaline phosphatase (ALP) level was markedly increased, while his serum calcium was slightly decreased and serum phosphate was normal. Skeletal radiographs of the lower extremities showed a progressive increase in skeletal density, but did not show any apparent deformity. Administration of nonsteroidal anti-inflammatory drugs led to a reduction in bone pain. Treatment with vitamin D3 and calcium decreased the number of episodes of sudden muscular weakness and maintained serum calcium within the normal range. Three years after the onset of the disease, bone mineral density of his lumbar vertebrae and left hip rose from 0.963 g/cm2 to 1.096 g/cm2, and from 0.938 g/cm2 to 1.383 g/cm2, respectively. His serum ALP level decreased from 2889 to 277 IU/L (normal range: 104-338) and serum calcium normalized. These findings were accompanied by a decrease in bone pain. This case and previous reports suggest that the skeletal tissue of this disease appears to be of good quality.


Subject(s)
Hepatitis C/complications , Osteosclerosis/complications , Aged , Alanine Transaminase/blood , Alkaline Phosphatase/blood , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Asian People , Aspartate Aminotransferases/blood , Bone Density , Bone and Bones/diagnostic imaging , Calcium/blood , Cholecalciferol/blood , Hepatitis C/blood , Humans , Male , Osteosclerosis/blood , Osteosclerosis/diagnostic imaging , Osteosclerosis/drug therapy , Pain/blood , Pain/drug therapy , Pain/etiology , Parathyroid Hormone/blood , Phosphorus/blood , Radiography , Whole Body Imaging
17.
Hypertension ; 42(6): 1183-90, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14670979

ABSTRACT

One of the major causes of end-stage renal diseases is hypertensive renal disease, in which enhanced renal prostaglandin (PG) E2 production has been shown. PGE2, a major arachidonic acid metabolite produced in the kidney, acts on 4 receptor subtypes, EP1 through EP4, but the pathophysiological importance of the PGE2/EP subtypes in the development of hypertensive renal injury remains to be elucidated. In this study, we investigated whether an orally active EP1-selective antagonist (EP1A) prevents the progression of renal damage in stroke-prone spontaneously hypertensive rats (SHRSP), a model of human malignant hypertension. Ten-week-old SHRSP, with established hypertension but with minimal renal damage, were given EP1A or vehicle for 5 weeks. After the treatment period, vehicle-treated SHRSP showed prominent proliferative lesions in arterioles, characterized by decreased alpha-smooth muscle actin expression in multilayered vascular smooth muscle cells. Upregulation of transforming growth factor-beta expression and tubulointerstitial fibrosis were also observed in vehicle-treated SHRSP. All these changes were dramatically attenuated in EP1A-treated SHRSP. Moreover, EP1A treatment significantly inhibited both increase in urinary protein excretion and decrease in creatinine clearance but had little effect on systemic blood pressure. These findings indicate that the PGE2/EP1 signaling pathway plays a crucial role in the development of renal injury in SHRSP. This study opens a novel therapeutic potential of selective blockade of EP1 for the treatment of hypertensive renal disease.


Subject(s)
Hypertension/complications , Kidney Diseases/etiology , Kidney/pathology , Receptors, Prostaglandin E/physiology , Animals , Blood Pressure , Cells, Cultured , Cinnamates , Cyclooxygenase 1 , Fibrosis , Glomerular Mesangium/cytology , Glomerular Mesangium/metabolism , Hypertension/enzymology , Hypertension/genetics , Isoenzymes/metabolism , Kidney/drug effects , Kidney/physiopathology , Kidney Diseases/pathology , Kidney Diseases/physiopathology , Membrane Proteins , Prostaglandin-Endoperoxide Synthases/metabolism , Proteinuria/etiology , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Receptors, Prostaglandin E/analysis , Receptors, Prostaglandin E/antagonists & inhibitors , Receptors, Prostaglandin E, EP1 Subtype
18.
Proc Natl Acad Sci U S A ; 100(7): 4132-7, 2003 Apr 01.
Article in English | MEDLINE | ID: mdl-12642666

ABSTRACT

Sickness evokes various neural responses, one of which is activation of the hypothalamo-pituitary-adrenal (HPA) axis. This response can be induced experimentally by injection of bacterial lipopolysaccharide (LPS) or inflammatory cytokines such as IL-1. Although prostaglandins (PGs) long have been implicated in LPS-induced HPA axis activation, the mechanism downstream of PGs remained unsettled. By using mice lacking each of the four PGE receptors (EP1-EP4) and an EP1-selective antagonist, ONO-8713, we showed that both EP1 and EP3 are required for adrenocorticotropic hormone release in response to LPS. Analysis of c-Fos expression as a marker for neuronal activity indicated that both EP1 and EP3 contribute to activation of neurons in the paraventricular nucleus of the hypothalamus (PVN). This analysis also revealed that EP1, but not EP3, is involved in LPS-induced activation of the central nucleus of the amygdala. EP1 immunostaining in the PVN revealed its localization at synapses on corticotropin-releasing hormone-containing neurons. These findings suggest that EP1- and EP3-mediated neuronal pathways converge at corticotropin-releasing hormone-containing neurons in the PVN to induce HPA axis activation upon sickness.


Subject(s)
Adrenocorticotropic Hormone/metabolism , Endotoxins/toxicity , Lipopolysaccharides/toxicity , Paraventricular Hypothalamic Nucleus/physiology , Receptors, Prostaglandin E/deficiency , Receptors, Prostaglandin E/physiology , Synapses/physiology , Animals , Bacterial Infections , Corticotropin-Releasing Hormone/analysis , Cyclooxygenase 1 , Cyclooxygenase 2 , Gene Expression Regulation/drug effects , Genes, fos , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/physiology , Isoenzymes/metabolism , Membrane Proteins , Mice , Mice, Knockout , Neurons/physiology , Pituitary-Adrenal System/drug effects , Pituitary-Adrenal System/physiology , Prostaglandin-Endoperoxide Synthases/metabolism , Receptors, Prostaglandin E/genetics , Receptors, Prostaglandin E, EP1 Subtype , Receptors, Prostaglandin E, EP2 Subtype , Receptors, Prostaglandin E, EP3 Subtype , Receptors, Prostaglandin E, EP4 Subtype , Reverse Transcriptase Polymerase Chain Reaction
19.
J Am Soc Nephrol ; 13(7): 1757-65, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12089371

ABSTRACT

Local production of prostaglandins (PGs) in the kidney is increased in clinical and experimental diabetic nephropathy, but the role of PGs in the pathogenesis and progression of diabetic nephropathy has remained unclear. It is here shown that an orally active antagonist selective for the PGE receptor EP1 subtype potently prevents the progression of nephropathy in streptozotocin-induced diabetic rats. The effects are shown by ameliorated renal and glomerular hypertrophy, decreased mesangial expansion, inhibited transcriptional activation of transforming growth factor-beta (TGF-beta) and fibronectin, and complete suppression of proteinuria. In vitro, this agent completely inhibits TGF-beta and fibronectin upregulation in mesangial cells cultured under high-glucose conditions. These data indicate that the PGE2-EP1 system plays a crucial role in the development of diabetic renal injury in rats. It is further shown that both the EP1 antagonist and aspirin, a nonselective PG synthase inhibitor, markedly attenuate mesangial expansion, whereas only the EP1 antagonist inhibits glomerular hypertrophy and proteinuria, which suggests that these changes are caused by different mechanisms. This study reveals a potential usefulness of selective EP1 blockade as a novel therapeutic strategy for diabetic nephropathy and also brings a new insight into our understanding of this disease.


Subject(s)
Cinnamates/pharmacology , Diabetic Nephropathies/prevention & control , Receptors, Prostaglandin E/antagonists & inhibitors , Animals , Aspirin/pharmacology , Autocrine Communication , Cells, Cultured , Cyclooxygenase Inhibitors/pharmacology , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/urine , Dinoprostone/metabolism , Disease Progression , Fibronectins/metabolism , Glomerular Mesangium/drug effects , Glomerular Mesangium/pathology , Hypertrophy , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Kidney/physiopathology , Kidney Glomerulus/drug effects , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Proteinuria/urine , Rats , Rats, Wistar , Receptors, Prostaglandin E, EP1 Subtype , Tissue Distribution , Transforming Growth Factor beta/metabolism , Up-Regulation/drug effects
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