The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is frequently responsible for chronic hyponatremia in the elderly due to age-related disruption of the inhibitory component of brain osmoregulatory mechanisms. Recent research has indicated that chronic hyponatremia is associated with gait disturbances, increased falls, and bone fragility in humans, and we have found that chronic hyponatremia causes increased bone resorption and reduced bone mineral density in young rats. In this study, we used a model of SIADH to study multi-organ consequences of chronic hyponatremia in aged rats. Sustained hyponatremia for 18 weeks caused progressive reduction of bone mineral density by DXA and decreased bone ash calcium, phosphate and sodium contents at the tibia and lumbar vertebrae. Administration of 10-fold higher vitamin D during the last 8 weeks of the study compensated for the reduction in bone formation and halted bone loss. Hyponatremic rats developed hypogonadism, as indicated by slightly lower serum testosterone and higher serum FSH and LH concentrations, markedly decreased testicular weight, and abnormal testicular histology. Aged hyponatremic rats also manifested decreased body fat, skeletal muscle sarcopenia by densitometry, and cardiomyopathy manifested as increased heart weight and perivascular and interstitial fibrosis by histology. These findings are consistent with recent results in cultured osteoclastic cells, indicating that low extracellular sodium concentrations increased oxidative stress, thereby potentially exacerbating multiple manifestations of senescence. Future prospective studies in patients with SIADH may indicate whether these multi-organ age-related comorbidities may potentially contribute to the observed increased incidence of fractures and mortality in this population.

Because clinical data suggests that females may be more prone to hyponatremia from AVP-mediated antidiuresis, we investigated whether there are sex differences in the expression and function of the renal V 2R. In normal Sprague-Dawley rat kidneys, V 2R mRNA and protein expression was 2.6-and 1.7-fold higher, respectively, in females compared with males. To investigate the potential physiological implications of this sex difference, we studied changes in urine osmolality induced by the AVP V 2R agonist desmopressin. In response to different doses of desmopressin, there was a graded increase in urine osmolality and decrease in urine volume during a 24-h infusion. Females showed greater mean increases in urine osmolality and greater mean decreases in urine volume at 0.5 and 5.0 ng/h infusion rates. We also studied renal escape from antidiuresis produced by water loading in rats infused with desmopressin (5.0 ng/h). After 5 days of water loading, urine osmolality of both female and male rats escaped to the same degree physiologically, but V 2R mRNA and protein in female kidneys was reduced to a greater degree (Ϫ63% and Ϫ73%, respectively) than in males (Ϫ32% and Ϫ48%, respectively). By the end of the 5-day escape period, renal V2R mRNA and protein expression were reduced to the same relative levels in males and females, thereby abolishing the sex differences in V2R expression seen in the basal state. Our results demonstrate that female rats express significantly more V2R mRNA and protein in kidneys than males, and that this results physiologically in a greater sensitivity to V2R agonist administration. The potential pathophysiological implications of these results are that females may be more susceptible to the development of dilutional hyponatremia because of a greater sensitivity to endogenously secreted AVP. renal escape; desmopressin; hyponatremia THE PRIME DETERMINANT OF WATER homeostasis in animals and man is the regulation of urinary free water excretion by circulating plasma levels of the hormone arginine vasopressin (AVP). AVP is a nine-amino acid peptide that is synthesized in magnocellular neural cells located in the hypothalamus. The synthesized peptide is enzymatically cleaved from its prohormone and is transported to the posterior pituitary where it is stored within neurosecretory granules until specific stimuli cause secretion of AVP into the bloodstream (23). Antidiuresis then occurs via interaction of the circulating hormone with AVP V 2 receptors (V 2 Rs) in the kidney, which results in increased water permeability of the collecting duct through the insertion aquaporin-2 (AQP2) water channels into the apical membranes of renal collecting duct principal cells (19). The importance of AVP in water homeostasis is underscored by the pathophysiology that occurs when AVP, or AVP-mediated receptor activation, is either deficient or excessive (27).The most common disorder of AVP dysregulation encountered in clinical medicine is hypoosmolar hyponatremia. Studies of hyponatremia in hospitalized patients have ...

Sex steroids influence the development and function of the songbird brain. Developmentally, the neural circuitry underlying song undergoes masculine differentiation under the influence of estradiol. In adults, estradiol stimulates song behavior and the seasonal growth of song control circuits. There is good reason to believe that these neuroactive estrogens are synthesized in the brain. At all ages, estrogens could act at the lateral ventricle, during migration, or where song nuclei exist or will form. We investigated the activity of two critical steroidogenic enzymes, 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD) and aromatase, using a slice culture system. Sagittal brain slices were collected from juvenile (posthatch day 20) and adult zebra finches containing either the lateral ventricle, where neurons are born, or the telencephalic song nuclei HVC and RA. The slices were incubated with 3 H dehydroepiandrosterone or 3 H-androstenedione. Activity was determined by isolating certain products of 3βHSD (5α-androstanedione, 5β-androstanedione, estrone, and estradiol) and aromatase (estrone and estradiol). Activities of both 3βHSD and aromatase were detected in all slices and were confirmed using specific enzyme inhibitors. We found no significant difference in activity between adult males and females in either region for either enzyme. Juvenile female slices containing the lateral ventricle, however, showed greater levels of 3βHSD activity than did similar slices from age-matched males. Determination of the activity of these critical steroidogenic enzymes in slice culture has implications for the role of neurosteroids in brain development.

SUMMARY Prorenin is secreted by mammalian cells transfected with a human preprorenin expression construct. The purpose of this investigation was to compare the physicochemical properties of expressed prorenin in culture medium with the known characteristics of human inactive renin, which accounts for nearly half the renin in plasma and kidney. We found that expressed human prorenin strongly resembles human renal and plasma inactive renin. The expressed prorenin was inactive and could be equally activated by acid (dialysis to pH 3.3) or trypsin. Acid activation was completely reversible; reexposure to acid could reactivate the expressed inactive renin. Exposure to cold ( -5°C for 3 days) could also activate expressed renin. The Michaelis-Menten constant of acid-activated expressed renin with sheep substrate was 0.29 /JLM, and the pH optimum was 7.8. Expressed inactive renin bound to a cibacron-blue affinity column and could be eluted with 0.5M NaCl. All the above characteristics resemble those of human renal and plasma inactive renin. In addition, the molecular weight of expressed prorenin and human chorionic renin was 47,000, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and 46,000, as measured by high-performance liquid chromatography. These data, taken together with the published observation that native human inactive renin cross-reacts with antibodies generated against amino acid sequences in the prosegment of renin, provide strong support for the hypothesis that human inactive renin is prorenin. 3 4 Indeed, it has been suggested that the syndrome may result from an inability to convert inactive renin to active renin. To understand such defects in renin secretion, it is important to identify the physiological role of inactive renin and to understand the relationships between the active and inactive forms of the enzyme. 7 like polypeptide hormone-secreting tumors, which produce large quantities of prohormone. Second, absolute levels of inactive renin have been found to change with perturbation of the renin system; for example, with marked, acute stimulation of renin, such as that which occurs with inhibition of converting enzyme, there is a reciprocal drop in inactive renin while active renin rises.8 Third, antibodies developed against pure human renal renin cross-react with inactive renin. 9 l0 Fourth, pulse-labeling studies in mouse submandibular gland, which makes large quantities of renin, indicate that renin is synthesized in two forms -preprorenin and prorenin, both of which are inactive."" 13 Fifth, peptide mapping suggests that human renal inactive renin is a renin zymogen.14 Finally, antibodies generated against synthetic peptides derived from the prosegment of human prorenin react with human inactive renin.

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