Gut bacteria convert glucocorticoids into progestins in the presence of hydrogen gas.

Recent studies suggest that human-associated bacteria interact with host-produced steroids, but the mechanisms and physiological impact of such interactions remain unclear. Here, we show that the human gut bacteria Gordonibacter pamelaeae and Eggerthella lenta convert abundant biliary corticoids into progestins through 21-dehydroxylation, thereby transforming a class of immuno- and metabo-regulatory steroids into a class of sex hormones and neurosteroids. Using comparative genomics, homologous expression, and heterologous expression, we identify a bacterial gene cluster that performs 21-dehydroxylation. We also uncover an unexpected role for hydrogen gas production by gut commensals in promoting 21-dehydroxylation, suggesting that hydrogen modulates secondary metabolism in the gut. Levels of certain bacterial progestins, including allopregnanolone, better known as brexanolone, an FDA-approved drug for postpartum depression, are substantially increased in feces from pregnant humans. Thus, bacterial conversion of corticoids into progestins may affect host physiology, particularly in the context of pregnancy and women's health.

Inshore and offshore marine migration pathways of Atlantic salmon post-smolts from multiple rivers in Scotland, England, Northern Ireland, and Ireland.

The migratory behavior of Atlantic salmon (Salmo salar) post-smolts in coastal waters is poorly understood. In this collaborative study, 1914 smolts, from 25 rivers, in four countries were tagged with acoustic transmitters during a single seasonal migration. In total, 1105 post-smolts entered the marine study areas and 438 (39.6%) were detected on a network of 414 marine acoustic receivers and an autonomous underwater vehicle. Migration pathways (defined as the shortest distance between two detections) of up to 575 km and over 100 days at sea were described for all 25 populations. Post-smolts from different rivers, as well as individuals from the same river, used different pathways in coastal waters. Although difficult to generalize to all rivers, at least during the year of this study, no tagged post-smolts from rivers draining into the Irish Sea were detected entering the areas of sea between the Hebrides and mainland Scotland, which is associated with a high density of finfish aquaculture. An important outcome of this study is that a high proportion of post-smolts crossed through multiple legislative jurisdictions and boundaries during their migration. This study provides the basis for spatially explicit assessment of the impact risk of coastal pressures on salmon during their first migration to sea.

Role of gut metabolism of adrenal corticosteroids and hypertension: clues gut-cleansing antibiotics give us.

Intestinal bacteria can metabolize sterols, bile acids, steroid hormones, dietary proteins, fiber, foodstuffs, and short chain fatty acids. The metabolic products generated by some of these intestinal bacteria have been linked to a number of systemic diseases including obesity with Type 2 diabetes mellitus, some forms of inflammation, and more recently, systemic hypertension. In this review, we primarily focus on the potential role selected gut bacteria play in metabolizing the endogenous glucocorticoids corticosterone and cortisol. Those generated steroid metabolites, when reabsorbed in the intestine back into the circulation, produce biological effects most notably as inhibitors of 11ß-hydroxysteroid dehydrogenase (11ß-HSD) types 1 and 2. Inhibition of the dehydrogenase actions of 11ß-HSD, particularly in kidney and vascular tissue, allows both corticosterone and cortisol the ability to bind to and activate mineralocorticoid receptors with attended changes in sodium handling and vascular resistance leading to increases in blood pressure. In several animal models of hypertension, administration of gut-cleansing antibiotics results in transient resolution of hypertension and transfer of intestinal contents from a hypertensive animal to a normotensive animal produces hypertension in the recipient. Moreover, fecal samples from hypertensive humans transplanted into germ-free mice resulted in hypertension in the recipient mice. Thus, it appears that the intestinal microbiome may not just be an innocent bystander but certain perturbations in the type and number of bacteria may directly or indirectly affect hypertension and other diseases.

Au130-x Agx Nanoclusters with Non-Metallicity: A Drum of Silver-Rich Sites Enclosed in a Marks-Decahedral Cage of Gold-Rich Sites.

The synthesis and structure of atomically precise Au130-x Agx (average x=98) alloy nanoclusters protected by 55 ligands of 4-tert-butylbenzenethiolate are reported. This large alloy structure has a decahedral M54 (M=Au/Ag) core. The Au atoms are localized in the truncated Marks decahedron. In the core, a drum of Ag-rich sites is found, which is enclosed by a Marks decahedral cage of Au-rich sites. The surface is exclusively Ag-SR; X-ray absorption fine structure analysis supports the absence of Au-S bonds. The optical absorption spectrum shows a strong peak at 523 nm, seemingly a plasmon peak, but fs spectroscopic analysis indicates its non-plasmon nature. The non-metallicity of the Au130-x Agx nanocluster has set up a benchmark to study the transition to metallic state in the size evolution of bimetallic nanoclusters. The localized Au/Ag binary architecture in such a large alloy nanocluster provides atomic-level insights into the Au-Ag bonds in bimetallic nanoclusters.

Description and experimental transmission of Tetracapsuloides vermiformis n. sp. (Cnidaria: Myxozoa) and guidelines for describing malacosporean species including reinstatement of Buddenbrockia bryozoides n. comb. (syn. Tetracapsula bryozoides).

This paper provides the first detailed description of a Tetracapsuloides species, Tetracapsuloides vermiformis n. sp., with vermiform stages in the bryozoan host, Fredericella sultana, and its experimental transmission from F. sultana to Cyprinus carpio. The suitability of morphological, biological and 18S rDNA sequence data for discrimination between malacosporean species is reviewed and recommendations are given for future descriptions. Presently, malacosporean species cannot be differentiated morphologically due to their cryptic nature and the lack of differential characters of spores and spore-forming stages in both hosts. We examined biological, morphological and molecular characters for the present description and for revising malacosporean taxonomy in general. As a result, Buddenbrockia plumatellae was split into two species, with its sac-like stages being ascribed to Buddenbrockia bryozoides n. comb. In addition to ribosomal DNA sequences multiple biological features rather than morphological characters are considered essential tools to improve malacosporean taxonomy in the future according to our analysis of the limited traits presently available.

How Children Perceive the Acoustic Environment of Their School.

OBJECTIVE: Children's own ratings and opinions on their schools sound environments add important information on noise sources. They can also provide information on how to further improve and optimize children's learning situation in their classrooms. This study reports on the Swedish translation and application of an evidence-based questionnaire that measures how children perceive the acoustic environment of their school. STUDY DESIGN: The Swedish version was made using a back-to-back translation. Responses on the questionnaire along with demographic data were collected for 149 children aged 9-13 years of age. RESULTS: The Swedish translation of the questionnaire can be reduced from 93 to 27 items. The 27 items were distributed over five separate factors measuring different underlying constructs with high internal consistency and high inter-item correlations. The responses demonstrated that the dining hall/canteen and the corridors are the school spaces with the poorest listening conditions. The highest annoyance was reported for tests and reading; next, student-generated sounds occur more frequently within the classroom than any sudden unexpected sounds, and finally, road traffic noise and teachers in adjoining classrooms are the most frequently occurring sounds from outside the classroom. Several demographic characteristics could be used to predict the outcome on these factors. CONCLUSION: The findings suggest that crowded spaces are most challenging; the children themselves generate most of the noise inside the classroom, but it is also common to hear road traffic noise and teachers in adjoining classrooms. The extent of annoyance that noise causes depends on the task but seems most detrimental in tasks, wherein the demands of verbal processing are higher. Finally, children with special support seem to report that they are more susceptible to noise than the typical child.

Parental comparison of the prosodic and paralinguistic ability of children with cochlear implants and their normal hearing siblings.

The everyday communication of children is commonly observed by their parents. This paper examines the responses of parents (n=18) who had both a Cochlear Implant (CI) and a Normal Hearing (NH) child. Through an online questionnaire, parents rated the ability of their children on a gamut of speech communication competencies encountered in everyday settings. Comparative parental ratings of the CI children were significantly poorer than those of their NH siblings in speaker recognition, happy and sad emotion, and question versus statement identification. Parents also reported that they changed the vocal effort and the enunciation of their speech when they addressed their CI child and that their CI child consistently responded when their name was called in normal, but not in noisy backgrounds. Demographic factors were not found to be linked to the parental impressions.

Spondyloarthropathies That Mimic Ankylosing Spondylitis: A Narrative Review.

Ankylosing spondylitis is the most common type of seronegative inflammatory spondyloarthropathy often presenting with low back or neck pain, stiffness, kyphosis and fractures that are initially missed on presentation; however, there are other spondyloarthropathies that may present similarly making it a challenge to establish the correct diagnosis. Here, we will highlight the similarities and unique features of the epidemiology, pathophysiology, presentation, radiographic findings, and management of seronegative inflammatory and metabolic spondyloarthropathies as they affect the axial skeleton and mimic ankylosing spondylitis. Seronegative inflammatory spondyloarthropathies such as psoriatic arthritis, reactive arthritis, noninflammatory spondyloarthropathies such as diffuse idiopathic skeletal hyperostosis, and ochronotic arthritis resulting from alkaptonuria can affect the axial skeleton and present with symptoms similar those of ankylosing spondylitis. These similarities can create a challenge for providers as they attempt to identify a patient's condition. However, there are characteristic radiographic findings and laboratory tests that may help in the differential diagnosis. Axial presentations of seronegative inflammatory, non-inflammatory, and metabolic spondyloarthropathies occur more often than previously thought. Identification of their associated symptoms and radiographic findings are imperative to effectively diagnose and properly manage patients with these diseases.

Ultrafast Preparation of Nonequilibrium FeNi Spinels by Magnetic Induction Heating for Unprecedented Oxygen Evolution Electrocatalysis.

Carbon-supported nanocomposites are attracting particular attention as high-performance, low-cost electrocatalysts for electrochemical water splitting. These are mostly prepared by pyrolysis and hydrothermal procedures that are time-consuming (from hours to days) and typically difficult to produce a nonequilibrium phase. Herein, for the first time ever, we exploit magnetic induction heating-quenching for ultrafast production of carbon-FeNi spinel oxide nanocomposites (within seconds), which exhibit an unprecedentedly high performance towards oxygen evolution reaction (OER), with an ultralow overpotential of only +260 mV to reach the high current density of 100 mA cm-2. Experimental and theoretical studies show that the rapid heating and quenching process (ca. 103 K s-1) impedes the Ni and Fe phase segregation and produces a Cl-rich surface, both contributing to the remarkable catalytic activity. Results from this study highlight the unique advantage of ultrafast heating/quenching in the structural engineering of functional nanocomposites to achieve high electrocatalytic performance towards important electrochemical reactions.

Aldosterone-induced fibrosis in the kidney: questions and controversies.

Over the years, aldosterone has been a favorite topic of renal physiologists given its role in the maintenance of body fluids. Investigators only recently are coming to appreciate a second proinflammatory and profibrotic role for this hormone. Mineralocorticoids such as aldosterone trigger a profibrotic process that in many respects mimics the early phase of wound healing. Depending on the type of cell involved, aldosterone may activate the profibrotic process through classic mineralocorticoid receptors, nonclassic membrane-associated mineralocorticoid receptors, and/or glucocorticoid receptors. In the kidney, the actions of aldosterone can be attenuated by 11-dehydro metabolites of endogenous glucocorticoids generated by isoforms of the enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD-1 and 11ß-HSD-2). Thus, the renal 11ß-HSD isoforms may have 2 functions: to block the improper activation of mineralocorticoid receptors by binding endogenous glucocorticoids and to synthesize agents that limit the actions of aldosterone. Although sodium in the diet has been implicated in aggravating aldosterone-induced renal fibrotic processes, preliminary findings are consistent with the view that aldosterone alone can initiate matrix production in renal tissue even in the absence of active sodium transport. Thus, there is a growing body of laboratory and clinical evidence supporting the use of inhibitors of aldosterone action in patients with both glomerular and tubular diseases.

Hydrogen generation from formic acid and alcohols using homogeneous catalysts.

This tutorial review describes recent progress in the development of homogeneous catalytic methodology for the direct generation of hydrogen gas from formic acid and alcohols.

Modulation of 11ß-hydroxysteroid dehydrogenase functions by the cloud of endogenous metabolites in a local microenvironment: The glycyrrhetinic acid-like factor (GALF) hypothesis.

11ß-Hydroxysteroid dehydrogenase (11ß-HSD)-dependent conversion of cortisol to cortisone and corticosterone to 11-dehydrocorticosterone are essential in regulating transcriptional activities of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Inhibition of 11ß-HSD by glycyrrhetinic acid metabolites, bioactive components of licorice, causes sodium retention and potassium loss, with hypertension characterized by low renin and aldosterone. Essential hypertension is a major disease, mostly with unknown underlying mechanisms. Here, we discuss a putative mechanism for essential hypertension, the concept that endogenous steroidal compounds acting as glycyrrhetinic acid-like factors (GALFs) inhibit 11ß-HSD dehydrogenase, and allow for glucocorticoid-induced MR and GR activation with resulting hypertension. Initially, several metabolites of adrenally produced glucocorticoids and mineralocorticoids were shown to be potent 11ß-HSD inhibitors. Such GALFs include modifications in the A-ring and/or at positions 3, 7 and 21 of the steroid backbone. These metabolites may be formed in peripheral tissues or by gut microbiota. More recently, metabolites of 11ß-hydroxy-Δ4androstene-3,17-dione and 7-oxygenated oxysterols have been identified as potent 11ß-HSD inhibitors. In a living system, 11ß-HSD isoforms are not exposed to a single substrate but to several substrates, cofactors, and various inhibitors simultaneously, all at different concentrations depending on physical state, tissue and cell type. We propose that this "cloud" of steroids and steroid-like substances in the microenvironment determines the 11ß-HSD-dependent control of MR and GR activity. A dysregulated composition of this cloud of metabolites in the respective microenvironment needs to be taken into account when investigating disease mechanisms, for forms of low renin, low aldosterone hypertension.

Direct fibrogenic effects of aldosterone on normotensive kidney: an effect modified by 11ß-HSD activity.

Aldosterone (Aldo) can be a profibrotic factor in cardiovascular and renal tissues. This study tests the hypothesis that prolonged Aldo exposure is able to directly induce fibrotic changes in the kidney of a normal nonhypertensive animal. Immortalized rat proximal tubule cells (IRPTC) containing 11ß-hydroxysteroid dehydrogenase (11ß-HSD1) but no mineralocorticoid receptors (MR) and mouse inner medullary collecting duct cells (IMCD) containing 11ß-HSD2 and MR were examined. IRPTC exposed to Aldo or corticosterone (10 nM) for 48 h demonstrated no change in collagen production as assessed by Sirius red staining. In contrast, IMCD treated with Aldo exhibited a marked increase in the expression of collagen, fibronectin, and connective tissue growth factor (CTGF), whereas corticosterone alone had no effect. The Aldo-induced overexperession of collagen, fibronectin, and CTGF was substantially attenuated by the MR antagonist RU-318 and by the 11ß-HSD end product 11-dehydrocorticosterone, but not by the glucocorticoid receptor antagonist RU-486. In vivo, early fibrotic changes with elevated collagen, fibronectin, and CTGF expression were observed in kidneys isolated from normotensive adrenalectomized mice receiving a continuous infusion of Aldo (8 µg·kg(-1)·day(-1)) for 1 wk. These changes were not present in corticosterone-treated mice. Aldo-induced changes were attenuated in adrenally intact mice and in mice treated with RU-318 or 11-dehydrocorticosterone. Thus, extended Aldo exposure produces fibrotic changes in cells containing MR and in normal kidneys. MR antagonists and the end products of 11ß-HSD attenuate these fibrogenic effects.

Cell formation by myxozoan species is not explained by dogma.

Eukaryotes form new cells through the replication of nuclei followed by cytokinesis. A notable exception is reported from the class Myxosporea of the phylum Myxozoa. This assemblage of approximately 2310 species is regarded as either basal bilaterian or cnidarian, depending on the phylogenetic analysis employed. For myxosporeans, cells have long been regarded as forming within other cells by a process referred to as endogenous budding. This would involve a nucleus forming endoplasmic reticulum around it, which transforms into a new plasma membrane, thus enclosing and separating it from the surrounding cell. This remarkable process, unique within the Metazoa, is accepted as occurring within stages found in vertebrate hosts, but has only been inferred from those stages observed within invertebrate hosts. Therefore, I conducted an ultrastructural study to examine how internal cells are formed by a myxosporean parasitizing an annelid. In this case, actinospore parasite stages clearly internalized existing cells; a process with analogies to the acquisition of endosymbiotic algae by cnidarian species. A subsequent examination of the myxozoan literature did not support endogenous budding, indicating that this process, which has been a central tenet of myxozoan developmental biology for over a century, is dogma.

FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases.

Insulin resistance and metabolic syndrome are rapidly expanding public health problems. Acting through the PI3K/Akt pathway, insulin and insulin-like growth factor-1 (IGF-1) inactivate FoxO transcription factors, a class of highly conserved proteins important in numerous physiological functions. However, even as FoxO is a downstream target of insulin, FoxO factors also control upstream signaling elements governing insulin sensitivity and glucose metabolism. Here, we report that sustained activation of either FoxO1 or FoxO3 in cardiac myocytes increases basal levels of Akt phosphorylation and kinase activity. FoxO-activated Akt directly interacts with and phosphorylates FoxO, providing feedback inhibition. We reported previously that FoxO factors attenuate cardiomyocyte calcineurin (PP2B) activity. We now show that calcineurin forms a complex with Akt and inhibition of calcineurin enhances Akt phosphorylation. In addition, FoxO activity suppresses protein phosphatase 2A (PP2A) and disrupts Akt-PP2A and Akt-calcineurin interactions. Repression of Akt-PP2A/B interactions and phosphatase activities contributes, at least in part, to FoxO-dependent increases in Akt phosphorylation and kinase activity. Resveratrol, an activator of Sirt1, increases the transcriptional activity of FoxO1 and triggers Akt phosphorylation in heart. Importantly, FoxO-mediated increases in Akt activity diminish insulin signaling, as manifested by reduced Akt phosphorylation, reduced membrane translocation of Glut4, and decreased insulin-triggered glucose uptake. Also, inactivation of the gene coding for FoxO3 enhances insulin-dependent Akt phosphorylation. Taken together, this study demonstrates that changes in FoxO activity have a dose-responsive repressive effect on insulin signaling in cardiomyocytes through inhibition of protein phosphatases, which leads to altered Akt activation, reduced insulin sensitivity, and impaired glucose metabolism.

Bacterial steroid-17,20-desmolase is a taxonomically rare enzymatic pathway that converts prednisone to 1,4-androstanediene-3,11,17-trione, a metabolite that causes proliferation of prostate cancer cells.

The adrenal gland has traditionally been viewed as a source of "weak androgens"; however, emerging evidence indicates 11-oxy-androgens of adrenal origin are metabolized in peripheral tissues to potent androgens. Also emerging is the role of gut bacteria in the conversion of C21 glucocorticoids to 11-oxygenated C19 androgens. Clostridium scindens ATCC 35,704 is a gut microbe capable of converting cortisol into 11-oxy-androgens by cleaving the side-chain. The desA and desB genes encode steroid-17,20-desmolase. Our prior study indicated that the urinary tract bacterium, Propionimicrobium lymphophilum ACS-093-V-SCH5 encodes desAB and converts cortisol to 11ß-hydroxyandrostenedione. We wanted to determine how widespread this function occurs in the human microbiome. Phylogenetic and sequence similarity network analyses indicated that the steroid-17,20-desmolase pathway is taxonomically rare and located in gut and urogenital microbiomes. Two microbes from each of these niches, C. scindens and Propionimicrobium lymphophilum, respectively, were screened for activity against endogenous (cortisol, cortisone, and allotetrahydrocortisol) and exogenous (prednisone, prednisolone, dexamethasone, and 9-fluorocortisol) glucocorticoids. LC/MS analysis showed that both microbes were able to side-chain cleave all glucocorticoids, forming 11-oxy-androgens. Pure recombinant DesAB from C. scindens showed the highest activity against prednisone, a commonly prescribed glucocorticoid. In addition, 0.1 nM 1,4-androstadiene-3,11,17-trione, bacterial side-chain cleavage product of prednisone, showed significant proliferation relative to vehicle in androgen-dependent growth LNCaP prostate cancer cells after 24 h (2.3 fold; P <  0.01) and 72 h (1.6 fold; P < 0.01). Taken together, DesAB-expressing microbes may be an overlooked source of androgens in the body, potentially contributing to various disease states, such as prostate cancer.

Myxobolus albi n. sp. (Myxozoa) from the Gills of the Common Goby Pomatoschistus microps Krøyer (Teleostei: Gobiidae).

A recent investigation into the myxozoan fauna of common gobies, Pomatoschistus microps, from the Forth Estuary in Scotland, revealed numerous myxosporean cysts within the gill cartilage. They were composed of polysporous plasmodia containing myxobolid spores that were morphologically different from the other known species of Myxobolus and from the myxosporeans previously recorded from this host (i.e. the ceratomyxid Ellipsomyxa gobii, infecting the gall bladder, and the kudoid Kudoa camarguensis, infecting the muscle tissues). Spores were ovoid, 9.4 x 9.1 microm with a thickness of 6.6 microm, with two pyriform polar capsules, the polar filaments of which had four to five turns. Molecular analysis of the parasite's small subunit rDNA region, based upon a contiguous sequence of 1,558 base pairs, discriminated it from other myxosporean species that have been characterized so far. A comparison of the spore morphology and the molecular sequences determined for this new isolate with other myxozoans described to date, confirmed its identity as a previously unknown myxobolid supporting the proposal that this isolate be elevated to the species level as a new species within the genus Myxobolus. A phylogenetic analysis places this new myxobolid, Myxobolus albi n. sp., in a basal position of a clade containing the majority of Henneguya spp. sequenced to date and various Myxobolus spp.

Interactions of mineralocorticoids and glucocorticoids in epithelial target tissues revisited.

The interplay between mineralocorticoids (MCs) and glucocorticoids (GCs) in sodium transporting epithelia is complex and only partially understood. In seminal papers published in the years soon after the discovery of aldosterone, various investigators experimentally observed that mineralocorticoid-induced renal sodium retention could only be reliably measured in adrenalectomized animals. Addition of endogenous GCs or their 11-dehydro metabolites blunted the antinatriuretic action of aldosterone and 11-dehydro-GCs decreased binding of aldosterone to mineralocorticoid receptors (MR). Under normal circumstances, endogenous GCs alone do not induce sodium transport in MC responsive epithelia yet these same GCs are able to activate MR and induce sodium transport if the enzyme 11beta-HSD2 is inhibited. Given the physiologic concentrations of both MCs and GCs, it is likely that the local epithelial cell exposure to GCs is great enough to allow GC binding to MR despite the presence of 11beta-HSD2. Thus other factors supplement the receptor selectivity role suggested for 11beta-HSD2. Why GCs bind to MR under one set of conditions and produce no effect and under different sets of conditions (11beta-HSD2 inhibition) elicit sodium transport remains a puzzle to be solved. What is clear is that a dual role for 11beta-HSD2 is emerging; first as the putative "guardian" over the MR reducing GC binding, and second as a source for 11-dehydro-GCs, which may serve as endogenously and locally produced "spironolactone-like substances", which may thus attenuate aldosterone-induced sodium transport.

Human renal 11beta-hydroxysteroid dehydrogenase 1 functions and co-localizes with COX-2.

The local renal metabolism of glucocorticoids (GCs) by isoforms of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1 and 11beta-HSD2) determines their biological effects. 11beta-HSD2, located in collecting duct epithelial cells of the mammalian and human kidney, serves as a putative "guardian" preventing GCs from binding to mineralocorticoid receptors. Various investigators have shown that both isoforms are present in kidney tissue from the rat, dog and other mammals. There is controversy as to whether 11beta-HSD1 exists and functions in human kidney. The current studies examine the locale and function of both isoforms in human kidney. The expression of 11beta-HSD1 was similar to that of 11beta-HSD2 by Western blot. Two distinct Lineweaver Burke plots could be drawn providing enzyme kinetics for both isoforms. The apparent Km for the NADP dependent 11beta-HSD1 enzyme was 0.42 muM while the apparent Km for the NAD dependent 11beta-HSD2 enzyme was 10.2 nM. Human renal 11beta-HSD1 appears to function as a dehydrogenase with no significant "reverse" reductase activity. Using immuno-histochemistry and Western blot analysis, 11beta-HSD1 was found to co-localize with COX-2 in proximal tubule cells; COX-2 was not seen with 11beta-HSD2 in cortical collecting duct. Thus, normal human kidney contains active 11beta-HSD1 and 11beta-HSD2. 11beta-HSD1 co-localizes with COX-2 in proximal tubule cells.

Co-localization of glucocorticoid metabolizing and prostaglandin synthesizing enzymes in rat kidney and liver.

AIMS: The kidney metabolizes endogenous glucocorticoids using one of 2 isoforms of the enzyme 11ss-Hydroxysteroid Dehydrogenase (11ss-HSD). 11ss-HSD1 is located in the later portion of the proximal tubule and interstitial cells and 11ss-HSD2 is found in the mineralocorticoid sensitive collecting duct. Both renal isoforms appear to function as dehydrogenases, inactivating glucocorticoids. Since our laboratory has established that both renal cyclo-oxygenase-2 (COX-2) and 11ss-HSD1 co-localize in human kidney, we hypothesized that the two enzymes might functionally interact and influence each other's expression and/or activity. METHODS AND RESULTS: Using immuno-histochemistry staining with specific antibodies, both enzymes co-localize in later segments of proximal tubules in rat kidney and in rat hepatocytes. There was no co-localization with 11ss-HSD2 in the kidney. The co-localization was confirmed by Western blot and by immuno-precipitation in cultured rat proximal tubular cells (IRPTC). IRPTC incubated with corticosterone 1 microM or with corticosterone 10 nM plus the 11ss-HSD inhibitor carbenoxolone 1 microM demonstrated a decrease in the expression of COX-2 by Western blot at 24 h. When IRPTC were exposed to the COX-2 inhibitor, celecoxib, 11ss-HSD1 dehydrogenase activity was inhibited in a dose dependent manner with an IC50 of 1.4 microM. Celecoxib 2 microM had minimal effect on reductase activity in liver slices. CONCLUSIONS: Thus, COX-2 and 11ss-HSD1 co-localize in renal proximal tubules and in hepatocytes. In the kidney, each can influence the biological function of the other. The NSAID celecoxib may exert some of its anti-inflammatory effects on the kidney by locally prolonging the biologic half-life of endogenous glucocorticoids.