Deficiency in Six2 during prenatal development is associated with reduced nephron number, chronic renal failure, and hypertension in Br/+ adult mice.

The Br/+ mutant mouse displays decreased embryological expression of the homeobox transcription factor Six2, resulting in hertitable renal hypoplasia. The purpose of this study was to characterize the renal physiological consequences of embryonic haploinsuffiency of Six2 by analyzing renal morphology and function in the adult Br heterozygous mutant. Adult Br/+ kidneys weighed 50% less than those from wild-type mice and displayed glomerulopathy. Stereological analysis of renal glomeruli showed that Br/+ kidneys had an average of 88% fewer glomeruli than +/+ kidneys, whereas individual glomeruli in Br/+ mice maintained an average volume increase of 180% compared with normal nephrons. Immunostaining revealed increased levels of endothelin-1 (ET-1), endothelin receptors A (ET(A)) and B (ET(B)), and Na-K-ATPase were present in the dilated renal tubules of mutant mice. Physiological features of chronic renal failure (CRF) including elevated mean arterial pressure, increased plasma creatinine, and dilute urine excretion were measured in Br/+ mutant mice. Electron microscopy of the Br/+ glomeruli revealed pathological alterations such as hypercellularity, extracellular matrix accumulation, and a thick irregular glomerular basement membrane. These results indicate that adult Br/+ mice suffer from CRF associated with reduced nephron number and renal hypoplasia, as well as glomerulopathy. Defects are associated with embryological deficiencies of Six2, suggesting that proper levels of this protein during nephrogenesis are critical for normal glomerular development and adult renal function.

Neuroendocrine regulation of fluid and electrolyte balance by ovarian steroids: contributions from central oestrogen receptors.

Like other hormonally mediated mechanisms, maintenance of body fluid osmolality requires integrated responses from multiple signals at various tissue locales, a large number of which are open to modulation by circulating endocrine factors including the ovarian steroid, oestrogens (E(2)). However, the precise mechanism and the site of action of E(2) in regulating fluid osmolality are not properly understood. More importantly, the biological significance of this action is not clear and the physiological circumstances in which this modulation is engaged remain incomplete. The demonstration of oestrogen receptors (ER) in neural tissues that bear no direct relation to reproduction led us to examine and characterise the expression of ER in brain nuclei that are critical for the maintenance of fluid osmolality. In the rat, ERbeta is prominently expressed in the vasopressin magnocellular neuroendocrine cells of the hypothalamus, whereas ERalpha is localised extensively in the sensory circumventricular organ neurones in the basal forebrain. These nuclei are the primary brain sites that are engaged in defense of fluid perturbation, thus providing a neuroendocrine basis for oestrogenic influence on body fluid regulation. Plasticity in receptor expression that accompanies fluid disturbances at these central loci suggests the functional importance of the receptors and implicates E(2) as one of the fluid regulating hormones in water homeostasis.

Depletion of oestrogen receptor-beta expression in magnocellular arginine vasopressin neurones by hypovolaemia and dehydration.

Oestrogen receptor (ER)-beta expression correlates inversely with osmotic control of arginine vasopressin (AVP) release such that cellular dehydration induced by 72 h of 2% saline consumption depletes ER-beta in the magnocellular AVP neurones in the supraoptic (SON) and paraventricular nuclei (PVN). The current studies were performed to determine whether other pathways that stimulate AVP release, such as hypovolaemia, also regulate ER-beta expression in these nuclei, and to evaluate the time course of the change in ER-beta expression during water deprivation and subsequent rehydration. ER-beta expression was evaluated immunocytochemically. In rats made hypovolaemic with a subcutaneous injection of 40% polyethylene glycol (PEG), a significant depletion of ER-beta in both SON and magnocellular PVN (P

Modulation of oestrogen receptor-beta mRNA expression in rat paraventricular and supraoptic nucleus neurones following adrenal steroid manipulation and hyperosmotic stimulation.

Magnocellular neurosecretory neurones in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei express oestrogen receptor beta (ERbeta) but not ERalpha. In the PVN, ERbeta is strongly expressed in the ventromedial parvocellular neurones projecting to the brainstem. We used quantitative in situ hybridization, with (35)S-labelled riboprobes, to study heterologous regulation by manipulating adrenal steroid hormones (72 h after adrenalectomy +/- corticosterone replacement; repeated stress: halothane inhalation, environmental cold, immobilization, each daily for 3 days) in male rats. Adrenalectomy increased ERbeta mRNA expression in the magnocellular PVN and SON, by 2.2 and 2.5-fold, respectively, with no effect in the ventromedial parvocellular PVN neurones. Corticosterone replacement partially prevented the increases in ERbeta mRNA expression in magnocellular PVN and SON neurones. Repeated stress over 72 h had no effect on ERbeta mRNA expression in the magnocellular PVN or SON, but increased expression 1.4-fold in the ventromedial parvocellular PVN neurones. Although consequences of hydromineral balance derangement after adrenalectomy may stimulate magnocellular neurones, strongly stimulating the neurones by giving intact male rats 2% saline to drink for 72 h decreased ERbeta mRNA expression in the magnocellular PVN and SON neurones by approximately 60%, and in the ventromedial parvocellular PVN neurones by 13%. Thus, ERbeta mRNA expression is negatively regulated by basal glucocorticoid secretion in magnocellular PVN and SON neurones, and positively regulated by stress in ventromedial parvocellular PVN neurones. However, ERbeta mRNA expression in magnocellular neurones is negatively linked to hyperosmotic stimulation of the neurones. The 6.25-fold variation in ERbeta mRNA expression in magnocellular neurones from salt-loading to adrenalectomy could alter their sensitivity to oestrogens. Consequently, regulation of oxytocin and vasopressin neurone activity via ERbeta is expected to vary according to their functional state and, in particular, on basal glucocorticoid actions.

Oestrogen receptor beta: role in neurohypophyseal neurones.

The robust expression of oestrogen receptor beta (ER-beta) in magnocellular vasopressin neurones has focused attention on the role of this receptor and the gonadal steroids in the regulation of vasopressin secretion. Although the effects of gonadal steroids on vasopressin secretion have been the subject of many studies, there is no consensus in the literature as to their role. Possible reasons for the diverse findings are discussed, including diversity in the types, site and level of expression of steroid receptors across species, gender and physiological conditions. The physiological regulation of expression is of particular interest because ER-beta mRNA expression in vasopressin neurones is inversely correlated to the osmotic state of the animal. Chronic hyperosmolality inhibits ER-beta mRNA expression in magnocellular vasopressin neurones, while chronic hypo-osmolality enhances expression. This is consistent with an inhibitory role for ER-beta because hyperosmolality is a potent stimulus for vasopressin secretion, whereas vasopressin secretion is maximally inhibited by chronic hypo-osmolality. An inhibitory role is also indicated by in vitro experiments demonstrating inhibition of osmotically stimulated vasopressin secretion by oestrogen and testosterone, and ER-beta mediated inhibition of NMDA-stimulated vasopressin secretion. The challenge remains to elucidate the mechanism of this inhibition, and to understand its significance for maintenance of whole-body fluid and electrolyte homeostasis.