RESUMO
In Scandinavia Puumala hantavirus causes nephropathia epidemica (NE), characterised by an acute debut of fever, headache, increasing back and abdominal pain, thrombocytopenia, increasing azotemia parameters, as well as microscopic haematuria and mild proteinuria. In some cases transitory myopia can be found. The diagnosis is made with a relevant clinical history and serology, and in most cases a kidney biopsy is not necessary. There is a risk of missing cases of NE as in this case, where a couple became infected by Puumala Hantavirus in a high-risk area but became ill in an area with a low prevalence.
Assuntos
Febre Hemorrágica com Síndrome Renal/virologia , Virus Puumala , Adulto , Creatinina/sangue , Feminino , Febre Hemorrágica com Síndrome Renal/sangue , Febre Hemorrágica com Síndrome Renal/diagnóstico , Febre Hemorrágica com Síndrome Renal/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Virus Puumala/isolamento & purificação , Virus Puumala/patogenicidade , Insuficiência Renal/virologiaRESUMO
BACKGROUND & AIMS: Suppression of the hypothalamic-pituitary-adrenal axis occurs in cirrhosis and cholestasis and is associated with increased concentrations of bile acids. We investigated whether this was mediated through bile acids acting to impair steroid clearance by inhibiting glucocorticoid metabolism by 5beta-reductase. METHODS: The effect of bile acids on glucocorticoid metabolism was studied in vitro in hepatic subcellular fractions and hepatoma cells, allowing quantitation of the kinetics and transcript abundance of 5beta-reductase. Metabolism was subsequently examined in vivo in rats following dietary manipulation or bile duct ligation. Finally, glucocorticoid metabolism was assessed in humans with obstructive jaundice. RESULTS: In rat hepatic cytosol, chenodeoxycholic acid competitively inhibited 5beta-reductase (K(i) 9.19+/-0.40 microM) and reduced its transcript abundance (in H4iiE cells) and promoter activity (reporter system, HepG2 cells). In Wistar rats, dietary chenodeoxycholic acid (1% w/w chow) inhibited hepatic 5beta-reductase activity, reduced urinary excretion of 3alpha,5beta-tetrahydrocorticosterone and reduced adrenal weight. Conversely, a fat-free diet suppressed bile acid levels and increased hepatic 5beta-reductase activity, supplementation of the fat-free diet with CDCA reduced 5beta-reductase activity, and urinary 3alpha,5beta-reduced corticosterone. Cholestasis in rats suppressed hepatic 5beta-reductase activity and transcript abundance. In eight women with obstructive jaundice, relative urinary excretion of 3alpha,5beta-tetrahydrocortisol was significantly lower than in healthy controls. CONCLUSION: These data suggest a novel role for bile acids in inhibiting hepatic glucocorticoid clearance, of sufficient magnitude to suppress hypothalamic-pituitary-adrenal axis activity. Elevated hepatic bile acids may account for adrenal insufficiency in liver disease.
Assuntos
Ácidos e Sais Biliares/farmacologia , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Icterícia Obstrutiva/tratamento farmacológico , Sistema Hipófise-Suprarrenal/fisiologia , 3-Hidroxiesteroide Desidrogenases/genética , Animais , Sequência de Bases , Ácidos e Sais Biliares/uso terapêutico , Ductos Biliares/fisiologia , Citosol/enzimologia , Feminino , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Icterícia Obstrutiva/metabolismo , Icterícia Obstrutiva/urina , Cinética , Ligadura , Fígado/enzimologia , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Ratos , Ratos Wistar , Tetra-Hidrocortisol/urina , Transcrição Gênica/efeitos dos fármacosRESUMO
The study was performed to elucidate the distribution and cellular localization of cyclooxygenase (COX)-2 in human kidney and to address localization of downstream targets for COX-derived prostanoids. Cortex and outer and inner medulla tissue were obtained from control kidneys (cancer specimens), kidneys with arterial stenosis, and kidneys of patients who received angiotensin II inhibition or acetylsalicylic acid. Ribonuclease protection assay and Western blot test revealed that COX-1 and -2 mRNA and protein were expressed in all regions of human kidney (mRNA ratio, cortex:outer medulla:inner medulla COX-1 1:3:20 and COX-2 1:1:3). In adult kidney, immunohistochemical labeling for COX-2 was associated with smooth muscle cells in pre- and postglomerular vessels and with endothelium, particularly in vasa recta and medullary capillaries. Western blot test confirmed COX-2 expression in renal artery. COX-2 had a similar localization in fetal kidney and was additionally observed in Henle's loop and macula densa. Human tissue arrays displayed COX-2 labeling of vascular smooth muscle in multiple extrarenal tissues. Vascular COX-2 expression was significantly increased in kidneys with arterial stenosis. COX-1 was colocalized with microsomal prostaglandin E(2) synthase (PGES) in collecting ducts, and PGES was also detected in macula densa cells. Vascular COX-2 was colocalized with prostaglandin E(2) EP4 receptors but not with EP2 receptors. Thus, renovascular COX-2 expression was a constitutive feature encountered in human kidneys at all ages, whereas COX-2 was seen in macula densa only in fetal kidney. Vascular COX-2 activity in human kidney and extrarenal tissues may support blood flow and affect vascular wall-blood interaction.
Assuntos
Endotélio Vascular/enzimologia , Isquemia/fisiopatologia , Isoenzimas/genética , Rim/irrigação sanguínea , Prostaglandina-Endoperóxido Sintases/genética , Receptores de Prostaglandina E/genética , Adulto , Angiotensina II/antagonistas & inibidores , Células Cultivadas , Ciclo-Oxigenase 2 , Endotélio Vascular/citologia , Endotélio Vascular/embriologia , Inibidores Enzimáticos/farmacologia , Feto , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Imuno-Histoquímica , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Rim/embriologia , Proteínas de Membrana , Prostaglandina-Endoperóxido Sintases/metabolismo , RNA Mensageiro/análise , Receptores de Prostaglandina E/metabolismo , Receptores de Prostaglandina E Subtipo EP4 , Obstrução da Artéria Renal/metabolismo , Obstrução da Artéria Renal/fisiopatologia , Artérias Umbilicais/citologia , Artérias Umbilicais/embriologia , Artérias Umbilicais/enzimologiaRESUMO
To investigate regional aspects of hypoxic regulation of adrenomedullin (AM) in kidneys, we mapped the distribution of AM in the rat kidney after hypoxia (normobaric hypoxic hypoxia, carbon monoxide, and CoCl(2) for 6 h), anemia (hematocrit lowered by bleeding) and after global transient ischemia for 1 h (unilateral renal artery occlusion and reperfusion for 6 and 24 h) and segmental infarct (6 and 24 h). AM expression and localization was determined in normal human kidneys and in kidneys with arterial stenosis. Hypoxia stimulated AM mRNA expression significantly in rat inner medulla (CO 13 times, 8% O(2) 6 times, and CoCl(2) 8 times), followed by the outer medulla and cortex. AM mRNA level was significantly elevated in response to anemia and occlusion-reperfusion. Immunoreactive AM was associated with the thin limbs of Henle's loop, distal convoluted tubule, collecting ducts, papilla surface epithelium, and urothelium. AM labeling was prominent in the inner medulla after CO and in the outer medulla after occlusion-reperfusion. The infarct border zone was strongly labeled for AM. In cultured inner medullary collecting duct cells, AM mRNA was significantly increased by hypoxia. AM mRNA was equally distributed in human kidney and AM was localized as in the rat kidney. In human kidneys with artery stenosis, AM mRNA was not significantly enhanced compared with controls, but AM immunoreactivity was observed in tubules, vessels, and glomerular cells. In summary, AM expression was increased in the rat kidney in response to hypoxic and ischemic hypoxia in keeping with oxygen gradients. AM was widely distributed in the human kidney with arterial stenosis. AM may play a significant role to counteract hypoxia in the kidney.