Roger W. Brown

Hypertension in mice lacking 11β-hydroxysteroid dehydrogenase type 2

Deficiency of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in humans leads to the syndrome of apparent mineralocorticoid excess (SAME), in which cortisol illicitly occupies mineralocorticoid receptors, causing sodium retention, hypokalemia, and hypertension. However, the disorder is usually incompletely corrected by suppression of cortisol, suggesting additional and irreversible changes, perhaps in the kidney. To examine this further, we produced mice with targeted disruption of the 11beta-HSD2 gene. Homozygous mutant mice (11beta-HSD2(-/-)) appear normal at birth, but approximately 50% show motor weakness and die within 48 hours. Both male and female survivors are fertile but exhibit hypokalemia, hypotonic polyuria, and apparent mineralocorticoid activity of corticosterone. Young adult 11beta-HSD2(-/-) mice are markedly hypertensive, with a mean arterial blood pressure of 146 +/- 2 mmHg, compared with 121 +/- 2 mmHg in wild-type controls and 114 +/- 4 mmHg in heterozygotes. The epithelium of the distal tubule of the nephron shows striking hypertrophy and hyperplasia. These histological changes do not readily reverse with mineralocorticoid receptor antagonism in adulthood. Thus, 11beta-HSD2(-/-) mice demonstrate the major features of SAME, providing a unique rodent model to study the molecular mechanisms of kidney resetting leading to hypertension.

Dietary Electrolyte–Driven Responses in the Renal WNK Kinase Pathway In Vivo

WNK1 and WNK4 are unusual serine/threonine kinases with atypical positioning of the catalytic active-site lysine (WNK: With-No-K[lysine]). Mutations in these WNK kinase genes can cause familial hyperkalemic hypertension (FHHt), an autosomal dominant, hypertensive, hyperkalemic disorder, implicating this novel WNK pathway in normal regulation of BP and electrolyte balance. Full-length (WNK1-L) and short (WNK1-S) kinase-deficient WNK1 isoforms previously have been identified. Importantly, WNK1-S is overwhelmingly predominant in kidney. Recent Xenopus oocyte studies implicate WNK4 in inhibition of both thiazide-sensitive co-transporter-mediated Na+ reabsorption and K+ secretion via renal outer medullary K+ channel and now suggest that WNK4 is inhibited by WNK1-L, itself inhibited by WNK1-S. This study examined WNK pathway gene expression in mouse kidney and its regulation in vivo. Expression of WNK1-S and WNK4 is strongest in distal tubule, dropping sharply in collecting duct and with WNK4 also expressed in thick ascending limb and the macula densa. These nephron segments that express WNK1-S and WNK4 mRNA have major influence on long-term NaCl reabsorption, BP, K+, and acid-base balance, processes that all are disrupted in FHHt. In vivo, this novel WNK pathway responds with significant upregulation of WNK1-S and WNK4 with high K+ intake and reduction in WNK1-S on chronic lowering of K+ or Na+ intake. A two-compartment distal nephron model explains these in vivo findings and the pathophysiology of FHHt well, with WNK and classic aldosterone pathways responding to drivers from K+ balance, extracellular volume, and aldosterone and cross-talk through distal Na+ delivery regulating electrolyte balance and BP.

Tissue-Specific Messenger Ribonucleic Acid Expression of 11β-Hydroxysteroid Dehydrogenase Types 1 and 2 and the Glucocorticoid Receptor within Rat Placenta Suggests Exquisite Local Control of Glucocorticoid Action1

Placental 11β-hydroxysteroid dehydrogenase (11β-HSD) regulates transplacental passage of maternal glucocorticoids to the fetus and is thus a key determinant of fetal glucocorticoid levels. It has also been proposed that placental 11β-HSD expression may influence local glucocorticoid actions by regulating access of corticosterone to the glucocorticoid receptor (GR) or mineralocorticoid receptor (MR). Therefore, the present study used a rat model to assess whether the GR or MR are coexpressed with the two forms of 11β-HSD (types 1 and 2) in the placental labyrinth zone, the major site of maternal-fetal transfer, and in the basal zone, the primary site of placental hormone synthesis. In situ hybridization analysis was used to assess messenger RNA (mRNA) expression for the GR, MR, 11β-HSD-1, and 11β-HSD-2 in the two placental zones on days 16, 19 and 22 of pregnancy (term = day 23). Whereas expression of the GR appeared relatively unchanged in both zones at these three stages of pregnancy, that of 11β-HSD-1 c...

Sgk1 Gene Expression in Kidney and Its Regulation by Aldosterone: Spatio-Temporal Heterogeneity and Quantitative Analysis

The serine-threonine kinase sgk1 was recently identified as a gene rapidly induced by mineralocorticoids, resulting in increased sodium transport in vitro. To carefully localize and quantify the renal sgk1 expression response to aldosterone, in situ hybridization was performed on kidneys of mice having aldosterone excess over a range of doses and durations. In control and adrenalectomized animals, the glomeruli and inner medullary collecting ducts were the major sites of sgk1 expression, which was maintained independent of aldosterone. Sgk1 upregulation induced by aldosterone excess exhibited spatio-temporal heterogeneity. Both acute (3-h) and chronic (6-d) aldosterone excess stimulated sgk1 expression in the distal nephron, i.e., from the distal convoluted tubules through to the outer medullary collecting ducts. Treatments for 6 d with low sodium diet (0.03% [I]) and aldosterone infusions (50 microg/kg per d [II], 150 microg/kg per d [III], and 750 microg/kg per d [IV]) generated elevation of circulating aldosterone. Across these treatments (I through IV), the circulating level correlated with the progressive induction of sgk1 expression, with highly stimulated tubules first appearing in cortex (I) and continuing downward (II) until there was a strong stimulation throughout outer medulla (III and IV). Interestingly, chronic but not acute aldosterone excess caused a slight increase of sgk1 expression in glomerulus (30 to 50%; P < 0.01) and a dramatic downregulation in the initial portion of inner medulla, which could result from diminished interstitial osmolarity. Relative quantification (versus control) of sgk1 upregulation in individual tubules revealed: (1) a 1.8-fold increase of sgk1 mRNA at 3 h (150 microg/kg injection) and (2) a dose-dependence of chronic upregulation reaching a ceiling of eightfold elevation.

An Experimental Study of the Relative Importance of Acoustic Parameters for Auditory Speaker Recognition

Many previous experimenters, by manipulating parameters in isolation, have examined the potentiality of these parameters as speaker-characterizing features, not their relative habitual importance for speaker recognition in everyday life. The two experiments reported here investigate this relative importance by the simultaneous manipulation of parameters. Using synthetic speech in a voice similarity judgment format, the first experiment employs eight factors in a restricted factorial design, and the second a subset of four of these factors in a full factorial design. Results indicate that (i) fundamental-frequency mean, formant mean and formant bandwidth are the most important parameters, among those investigated, for speaker recognition, and (ii) although listeners differ in the average score recorded, they may be treated as reacting identically to changes in the factors. Implications for perception theory are outlined.

Glucocorticoid action in development

Purpose of reviewGlucocorticoid action in development is of special interest not just in understanding how tissues and organs mature but also because altered developmental glucocorticoid levels can have lifelong effects on physiology, with overexposure predisposing to adult disease. However, in defined situations antenatal glucocorticoid treatment can have very beneficial therapeutic effects, especially accelerating fetal organ lung maturity in threatened premature birth. Recent findingsFull glucocorticoid sensitivity requires expression of receptors (glucocorticoid receptor and mineralocorticoid receptor). Tissue glucocorticoid levels derive from the output of both maternal and fetal adrenal glands and glucocorticoid metabolism in the placenta and fetal tissues. Two 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes show tissue-specific expression of glucocorticoid-inactivating (11β-HSD2) or glucocorticoid-reactivating (11β-HSD1) activity and so have important influence on tissue availability of active glucocorticoid. By mapping out the gene expression of these receptors and 11β-HSD enzymes, a highly regulated pattern of changes is revealed, indicating prominent tissue and gestational-age-specific changes in determinants of glucocorticoid sensitivity. Responses of developing tissues to glucocorticoids are far from fully understood, but evidence supports such variations in sensitivity. SummaryThis review focuses on three organs, illustrating how glucocorticoids may influence the developmental program running in mammalian organs which at key points may be highly glucocorticoid sensitive and at others glucocorticoid effects may no longer be reversible and so permanently program changes in tissue function. The specific circumstances and pathways by which glucocorticoids have long-lasting beneficial and harmful actions are not yet known, but intelligent studies modeling these matters in animals provide a way forward.

Memory and decision in speaker recognition

Two categorizations are presented of aspects of the speaker recognition field. The first examines the memory systems involved in experimental tasks and is based on a critical account of the taxonomy proposed by Bricker & Pruzansky (1976). The second deals with the decisions which listeners are required to make in the experimental situation. Finally, the differences between the experimental situation and the real world are examined.

Naturally too sympathetic to a bad diet

An ominous upward trend in obesity, diabetes, and associated hypertension and their consequences warns all of us of a burden in cardiovascular disease already well developed in the United States and sweeping across Europe, many parts of Asia, and beyond. It seems set to get worse. This epidemic