Angiotensin II and III metabolism and effects on steroid production in the HAC15 human adrenocortical cell line.

Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex under primary regulation by the renin-angiotensin system. Angiotensin II (A-II) acts through the angiotensin types 1 and 2 receptors (AT1R and AT2R). A-II is metabolized in different tissues by various enzymes to generate two heptapeptides A-III and angiotensin 1-7, which can then be catabolized into smaller peptides. A-II was more potent than A-III in stimulating aldosterone secretion in the adrenocortical cell line HAC15, and A-II, but not A-III, stimulated cortisol secretion. A-II stimulated mRNA expression of steroidogenic acute regulatory protein, 3ß-hydroxysteroid dehydrogenase, CYP11B1, and CYP11B2, whereas A-III stimulated 3ß-hydroxysteroid dehydrogenase, CYP11B1, and CYP11B2 but decreased the expression of CYP17A1 required for cortisol synthesis. The stimulation of aldosterone secretion by A-II and A-III was blocked by the AT1R receptor blocker, losartan, but not by an AT2R blocker. A-II was rapidly metabolized by the HAC15 cells to mainly to angiotensin 1-7, but not to A-III, and disappeared from the supernatant within 6 h. A-III was metabolized rapidly and disappeared within 1 h. In conclusion, A-II was not converted to A-III in the HAC15 cell and is the more potent stimulator of aldosterone secretion and cortisol of the two. A-III stimulated aldosterone secretion but not cortisol secretion.

Potassium channel mutant KCNJ5 T158A expression in HAC-15 cells increases aldosterone synthesis.

Primary aldosteronism is the most common cause of secondary hypertension, most frequently due to an aldosterone-producing adenoma or idiopathic hyperaldosteronism. Somatic mutations of the potassium channel KCNJ5 in the region of the selectivity filter have been found in a significant number of aldosterone-producing adenomas. There are also familial forms of primary aldosteronism, one of which, familial hyperaldosteronism type 3 which to date has been found in one family who presented with a severe abnormality in aldosterone and 18-oxocortisol production and hypertrophy and hyperplasia of the transitional zone of the adrenal cortex. In familial hyperaldosteronism type 3, there is a genomic mutation causing a T158A change of amino acids within the selectivity filter region of the KCNJ5 gene. We are reporting our studies demonstrating that lentiviral-mediated expression of a gene carrying the T158A mutation of the KCNJ5 in the HAC15 adrenal cortical carcinoma cell line causes a 5.3-fold increase in aldosterone secretion in unstimulated HAC15-KCNJ5 cells and that forskolin-stimulated aldosterone secretion was greater than that of angiotensin II. Expression of the mutated KCNJ5 gene decreases plasma membrane polarization, allowing sodium and calcium influx into the cells. The calcium channel antagonist nifedipine and the calmodulin inhibitor W-7 variably inhibited the effect. Overexpression of the mutated KCNJ5 channel resulted in a modest decrease in HAC15 cell proliferation. These studies demonstrate that the T158A mutation of the KCNJ5 gene produces a marked stimulation in aldosterone biosynthesis that is dependent on membrane depolarization and sodium and calcium influx into the HAC15 adrenal cortical carcinoma cells.

Características de las crisis epilépticas en niños con insuficiencia renal crónica terminal / Characteristics of seizures seen in children with terminal chronic renal failure

Las crisis epilépticas son complicaciones frecuentes en niños que padecen de Insuficiencia Renal Crónica Terminal (IRC-T). Objetivos: Describir la frecuencia y características de las crisis epilépticas en niños con IRC-T. Material y métodos: Estudio retrospectivo, tipo serie de casos. Se incluyeron 24 pacientes menores de 14 años de ambos sexos con IRC-T que presentaron al menos un episodio de crisis epiléptica, atendidos en el Hospital Nacional Cayetano Heredia entre enero de 1998 y marzo de 2006. Resultados: La frecuencia encontrada de crisis epiléptica en esta población fue de 24/18 (75 por ciento) se encontraban en tratamiento dialítico crónico al momento de presentarse la primera crisis epiléptica; las glomerulopatías fueron la etiología más frecuente de la IRC-T; la mayoría de niños (41.6 por ciento) presentaron crisis parciales, y el hallazgo tomográfico más frecuente fue la hemorragia intraparenquimal. Conclusiones: La frecuencia de crisis epilépticas en esta serie de niños con IRC-T es menor que la descrita en la literatura revisada.

Seizures are a frequent complication seen in children with Terminal Chronic Renal Failure. Objective: To describe the characteristics of seizures seen in the children with Terminal Chronic Renal Failure. Material and methods: Retrospective study, type series of cases. There were included 24, 14 year-old minor patients of both sexes by IRC-T who presented at least an episode of epileptic attack, attended in the Hospital Nacional Cayetano Heredia between January, 1998 and march, 200. Results: We found 24/188 (12.7 per cent) prevalence of seizures in the population, 18/24 (75 per cent) of children were on cvhronic dialysis while they present the first episode of seizures, the most frequent type of seizures were partial crisis (41.6 per cent); we found that the more frequent etiology of Terminal Chronic Renal Failure was glomerulopathies and the most frequent finding on the CT scan was the parenchymal hemorrhage. Conclusions: The frecuency of seizures in children with Terminal Chronic Renal Failure were less frequent than the frequency found in the revised literature.