Ontogeny of adrenal-like glucocorticoid synthesis pathway and of 20α-hydroxysteroid dehydrogenase in the mouse lung

BMC Research Notes

Yves Tremblay¹  Pierre R Provost¹  Eric Boucher¹ 

[1] Centre de Recherche en Biologie de la Reproduction (CRBR), Faculté de Médecine, Université Laval, Québec, QC, Canada

关键词: 11β-HSD;    Mineralocorticoid;    Steroidogenesis;    Progesterone;    Glucocorticoid;    Fetal;    Development;    Corticosterone;    11β-hydroxylase;    21-hydroxylase;   

Others  :  1134397
DOI  :  10.1186/1756-0500-7-119

 received in 2013-12-17, accepted in 2014-02-24,  发布年份 2014

【 摘 要 】

Background

Glucocorticoids exert recognized positive effects on lung development. The genes involved in the classical pathway of glucocorticoid synthesis normally occurring in adrenals were found to be expressed on gestation day (GD) 15.5 in the developing mouse lung. Recently, expression of two of these genes was also detected on GD 17.5 suggesting a more complex temporal regulation than previously expected. Here, we deepen the knowledge on expression of “adrenal” glucocorticoid synthesis genes in the mouse lung during the perinatal period and we also study expression of the gene encoding for the steroid inactivating enzyme 20α-hydroxysteroid dehydrogenase (20α-HSD).

Results

We performed an ontogenic study of P450scc, 3β-hydroxysteroid dehydrogenase/Δ⁵-Δ⁴ isomerase 1 (3β-HSD1), 21-hydroxylase, 11β-hydroxylase, 11β-HSD1, and 11β-HSD2 expression up to post natal day (PN) 15. The substrate (progesterone) and the product (deoxycorticosterone) of 21-hydroxylase are substrates of 20α-HSD, thus 20α-HSD (Akr1c18) gene expression was investigated. In lung samples collected between GD 15.5 and PN 15, 11β-hydroxylase was only detected on GD 15.5. In contrast, all the other tested genes were expressed throughout the analyzed period with different temporal expression patterns. P450scc, 21-hydroxylase, 20α-HSD and 11β-HSD2 mRNA levels increased after birth with different patterns including an increase from PN 3 with a possible sex difference for 21-hydroxylase mRNA. Also, the 21-hydroxylase protein was observed by Western blot in perinatal lungs with higher levels after birth.

Conclusion

Progesterone is present at high levels during gestation and the product of 21-hydroxylase, deoxycorticosterone, can bind the glucocorticoid receptor with an affinity close to that of corticosterone. Detection of 21-hydroxylase at the protein level during antenatal lung development is the first evidence that the adrenal-like glucocorticoid synthesis pathway detected during lung development has the machinery to produce glucocorticoids in the fetal lung. Glucocorticoids from lung 21-hydroxylase appear to modulate lung ontogenesis through paracrine/intracrine actions.

【 授权许可】

   
2014 Boucher et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Bolt RJ, Van Weissenbruch MM, Lafeber HN, de Wall HA D-v: Glucocorticoids and lung development in the fetus and preterm infant. Pediatr Pulmonol 2001, 32:76-91.
• [2]Venihaki M, Majzoub J: Animal models of CRH deficiency. Front Neuroendocrinol 1999, 20:122-145.
• [3]Wang J, Kuliszewski M, Yee W, Sedlackova L, Xu J, Tseu I, Post M: Cloning and expression of glucocorticoid-induced genes in fetal rat lung fibroblasts. J Biol Chem 1995, 270:2722-2728.
• [4]Cole TJ, Blendy JA, Monaghan AP, Krieglstein K, Schmid W, Aguzzi A, Fantuzzi G, Hummler E, Unsicker K, Schütz G: Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev 1995, 9:1608-1621.
• [5]Muglia L, Jacobson L, Dikkes P, Majzoub JA: Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need. Nature 1995, 373:427-432.
• [6]Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM: 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev 2004, 25:831-866.
• [7]Taves MD, Gomez-Sanchez CE, Soma KK: Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function. Am J Physiol Endocrinol Metab 2011, 301:E11-E24.
• [8]Provost PR, Tremblay Y: Genes involved in the adrenal pathway of glucocorticoid synthesis are transiently expressed in the developing lung. Endocrinology 2005, 146:2239-2245.
• [9]Stocco DM, Clark BJ: Regulation of the acute production of steroids in steroidogenic cells. Endocr Rev 1996, 17:221-244.
• [10]Simard M, Côté M, Provost PR, Tremblay Y: Expression of genes related to the hypothalamic-pituitary-adrenal axis in murine fetal lungs in late gestation. Reprod Biol Endocrinol 2010, 8:134. BioMed Central Full Text
• [11]Provost PR, Boucher E, Tremblay Y: Glucocorticoid metabolism in the developing lung: adrenal-like synthesis pathway. J Steroid Biochem Mol Biol 2013, 138C:72-80.
• [12]Giannopoulos G, Keichline D: Species-related differences in steroid-binding specificity of glucocorticoid receptors in lung. Endocrinology 1981, 108:1414-1419.
• [13]Hellal-Levy C, Couette B, Fagart J, Souque A, Gomez-Sanchez C, Rafestin-Oblin M: Specific hydroxylations determine selective corticosteroid recognition by human glucocorticoid and mineralocorticoid receptors. FEBS Lett 1999, 464:9-13.
• [14]Rupprecht R, Reul JM, van Steensel B, Spengler D, Soder M, Berning B, Holsboer F, Damm K: Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands. Eur J Pharmacol 1993, 247:145-154.
• [15]Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, Hochberg RB, McKay L, Renoir JM, Weigel NL, Wilson EM, McDonnell DP, Cidlowski JA: International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol Rev 2006, 58:782-797.
• [16]Shimada H, Miura K, Imamura Y: Characteristics and inhibition by flavonoids of 20alpha-hydroxysteroid dehydrogenase activity in mouse tissues. Life Sci 2006, 78:2931-2936.
• [17]Milewich L, Smith SL, MacDonald PC: Nonrespiratory functions of the human lung: in vitro metabolism of tritium-labeled progesterone and pregnenolone. J Clin Endocrinol Metab 1980, 50:507-515.
• [18]Hershkovitz L, Beuschlein F, Klammer S, Krup M, Weinstein Y: Adrenal 20alpha-hydroxysteroid dehydrogenase in the mouse catabolizes progesterone and 11-deoxycorticosterone and is restricted to the X-zone. Endocrinology 2007, 148:976-988.
• [19]Pelletier G, Luu-The V, Li S, Ren L, Labrie F: Sex-related expression of 20alpha-hydroxysteroid dehydrogenase mRNA in the adult mouse. J Histochem Cytochem 2003, 51:1425-1436.
• [20]Weisz J, Ward IL: Plasma testosterone and progesterone titers of pregnant rats, their male and female fetuses and neonatal offspring. Endocrinology 1980, 106:306-311.
• [21]Labrie F: At the cutting edge: intracrinology. Mol Cell Endocrinol 1991, 78:c113-C118.
• [22]Labrie F, Luu-The V, Lin SX, Simard J, Labrie C, El-Alfy M, Pelletier G, Belanger A: Intracrinology: role of the family of 17 beta-hydroxysteroid dehydrogenases in human physiology and disease. J Mol Endocrinol 2000, 25:1-16.
• [23]Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS: Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol 1994, 105:R11-R17.
• [24]Brown RW, Chapman KE, Kotelevtsev Y, Yau JL, Lindsay RS, Brett L, Leckie C, Murad P, Lyons V, Mullins JJ, Edwards CR, Seckl JR: Cloning and production of antisera to human placental 11 beta-hydroxysteroid dehydrogenase type 2. Biochem J 1996, 313:1007-1017.
• [25]Martinerie L, Munier M, Le Menuet D, Meduri G, Viengchareun S, Lombes M: The mineralocorticoid signaling pathway throughout development: expression, regulation and pathophysiological implications. Biochimie 2012, 95:148-157.
• [26]Hirasawa G, Sasano H, Suzuki T, Takeyama J, Muramatu Y, Fukushima K, Hiwatashi N, Toyota T, Nagura H, Krozowski ZS: 11Beta-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor in human fetal development. J Clin Endocrinol Metab 1999, 84:1453-1458.
• [27]Suzuki T, Sasano H, Suzuki S, Hirasawa G, Takeyama J, Muramatsu Y, Date F, Nagura H, Krozowski ZS: 11beta-hydroxysteroid dehydrogenase type 2 in human lung: possible regulator of mineralocorticoid action. J Clin Endocr Metab 1998, 83:4022-4025.
• [28]Mustafa SB, DiGeronimo RJ, Petershack JA, Alcorn JL, Seidner SR: Postnatal glucocorticoids induce alpha-ENaC formation and regulate glucocorticoid receptors in the preterm rabbit lung. Am J Physiol Lung Cell Mol Physiol 2004, 286:L73-L80.
• [29]Venkatesh VC, Katzberg HD: Glucocorticoid regulation of epithelial sodium channel genes in human fetal lung. Am J Physiol 1997, 273:L227-L233.
• [30]Chirgwin JJ, Przbyla AE, MacDonald RJ, Ritter WJ: Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 1979, 18:5294-5299.
• [31]Simard M, Boucher E, Provost PR, Tremblay Y: Minimization of PCR efficiency differences between standards and samples through dilution of PCR amplicons in reverse transcription buffer. Anal Biochem 2007, 362:142-144.
• [32]Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F: Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002, 3:RESEARCH0034.
• [33]Boucher E, Provost PR, Plante J, Tremblay Y: Androgen receptor and 17beta-HSD type 2 regulation in neonatal mouse lung development. Mol Cell Endocrinol 2009, 311:109-119.