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

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Sgk1 Gene Expression in Kidney and Its Regulation by Aldosterone: Spatio-Temporal Heterogeneity and Quantitative Analysis J Am Soc Nephrol 13: 1190–1198, 2002 Sgk1 Gene Expression in Kidney and Its Regulation by Aldosterone: Spatio-Temporal Heterogeneity and Quantitative Analysis JIANGHUI HOU, HELEN J. L. SPEIRS, JONATHAN R. SECKL, and ROGER W. BROWN Molecular Medicine Centre, Western General Hospital, Edinburgh, United Kingdom. Abstract. The serine-threonine kinase sgk1 was recently iden- ␮g/kg per d [II], 150 ␮g/kg per d [III], and 750 ␮g/kg per d tified as a gene rapidly induced by mineralocorticoids, result- [IV]) generated elevation of circulating aldosterone. Across ing in increased sodium transport in vitro. To carefully localize these treatments (I through IV), the circulating level correlated and quantify the renal sgk1 expression response to aldosterone, with the progressive induction of sgk1 expression, with highly in situ hybridization was performed on kidneys of mice having stimulated tubules first appearing in cortex (I) and continuing aldosterone excess over a range of doses and durations. In downward (II) until there was a strong stimulation throughout control and adrenalectomized animals, the glomeruli and inner outer medulla (III and IV). Interestingly, chronic but not acute medullary collecting ducts were the major sites of sgk1 ex- aldosterone excess caused a slight increase of sgk1 expression pression, which was maintained independent of aldosterone. in glomerulus (30 to 50%; P Ͻ 0.01) and a dramatic down- Sgk1 upregulation induced by aldosterone excess exhibited regulation in the initial portion of inner medulla, which could spatio-temporal heterogeneity. Both acute (3-h) and chronic result from diminished interstitial osmolarity. Relative quanti- (6-d) aldosterone excess stimulated sgk1 expression in the fication (versus control) of sgk1 upregulation in individual distal nephron, i.e., from the distal convoluted tubules through tubules revealed: (1) a 1.8-fold increase of sgk1 mRNA at 3 h to the outer medullary collecting ducts. Treatments for 6 d with (150 ␮g/kg injection) and (2) a dose-dependence of chronic low sodium diet (0.03% [I]) and aldosterone infusions (50 upregulation reaching a ceiling of eightfold elevation. Regulation of sodium reabsorption in kidney is crucial for the pathway of aldosterone action, leading to the finding of an maintenance of whole body fluid homeostasis. The Naϩ trans- early-response gene, sgk1 (serum/glucocorticoid kinase), the port induced by aldosterone, either in vivo or in vitro,is transcription of which is rapidly (Ͻ3 h) stimulated by aldoste- ϩ sensitive to the K -sparing diuretic amiloride, which is a rone excess (7). Intriguingly, sgk1 was shown to significantly ϩ potent blocker of the epithelial Na channel (ENaC) (1–3). elevate ENaC-mediated sodium transport via increasing the The major site of aldosterone action is in the cortical collecting surface expression of ENaC subunits in Xenopus oocytes (8), duct, including its initial portion. Receptor sites and metabolic which is in keeping with evidence suggesting sgk1 may facil- effects of mineralocorticoids have been documented through itate a similar increased apical translocation of ENaC in distal the second half of distal convoluted tubules (DCT) and in the nephron in vivo (9–10). Other stimuli, such as insulin, glu- connecting tubules and the medullary collecting ducts (4–5). cocorticoids, and cell volume change, were documented to Two phases are distinguished in its regulation of sodium trans- regulate sgk1 (11–14). These in vitro findings identify sgk1 as port: an early phase starting after a lag period of 20 to 60 min, a key gene in hormonal regulation of sodium transport in cells during which the preexisting channels and Na/K-ATPase of distal nephron. It thus becomes of great interest to determine Ͼ pumps are activated, and a late phase ( 2.5 h), which involves the distribution of sgk1 in intact kidney and study its hormonal increasing contribution from newly synthesized channel and regulation in vivo. pump proteins (6). Previous animal studies have been focusing on the short- In the A6 Xenopus cell line, which is a good model of term (0.5- to 4-h) effect of aldosterone on sgk1 expression mammalian distal nephron, efforts have been made to elucidate (7,15–16). First, we aim to elucidate whether regulation of sgk1 expression is consistent with playing a role in transduc- tion of aldosterone-driven sodium reabsorption in distal Received August 3, 2001. December 22, 2001. nephron in both short-term (acute) and chronic hyperaldoste- Correspondence to: Dr. Roger W. Brown, Molecular Medicine Centre, West- ern General Hospital, Edinburgh EH 2XU, United Kingdom. Phone: 44-131- ronism. Second, we look for evidence of other potential regu- 651-1024/1037; Fax: 44-131-651-1085; E-mail: [email protected] lators of and roles for sgk1 in kidney. In particular, sgk1 1046-6673/1305-1190 expression may exhibit an aldosterone dose dependence in Journal of the American Society of Nephrology such a way that a plateau or a peak occurs at a dose above Copyright © 2002 by the American Society of Nephrology which there is no further induction or even a fall off in the DOI: 10.1097/01.ASN.0000013702.73570.3B degree of sgk1 induction. This would be of particular interest, J Am Soc Nephrol 13: 1190–1198, 2002 Sgk1 Gene Expression in Kidney 1191 as it may identify a response moderating aldosterone-sgk1– ␮g/kg per d) for 6 or 21 d. To investigate the acute effects of driven sodium retention and imply that such a mechanism aldosterone, 150 ␮g/kg injections were given to mice 3 h before contributes to escape from aldosterone-induced Na retention. sacrifice. Additionally, one group of mice was kept on 0.03% low- Finally, these detailed studies on a wide range of aldosterone- sodium diet for 6 d. Table 1 gives details of these groups. related treatments will allow a clearer view of sgk1 expression and regulation along the nephron and will help to guide future Plasma Aldosterone Assay studies. To address these issues, we performed in situ hybrid- Blood samples were removed by cardiac puncture rapidly after ization using radiolabeled riboprobes, autoradiographic films, initiation of terminal anesthesia and centrifuged at 4°C for 10 min. Ϫ and silver grain counting, which are well-established means of Plasma was separated and stored at 20°C. Aldosterone was assayed using a 125I-RIA kit (DPC, Los Angeles, CA). relative quantitation of expression level (17). This approach allows comparison of sgk1 mRNA expression levels in renal regions and nephron segments. In Situ Hybridization On the basis of mouse sgk1 sequence (accession number: AF139638), primers were designed to amplify a fragment encompass- Materials and Methods ing a region (1091 to 1336 bp) that had no significant homology to Materials other sequences. Flanking T3 and T7 phage polymerase consensus Steroids, propylene glycol, DMSO, and molecular biology–grade sites were introduced by nested PCR as described previously (18). chemicals were purchased from Sigma Chemical Company (Poole, Single-stranded [35S]UTP-labeled RNA probes were generated using Dorset, UK), 1-kb ladder DNA size markers and synthesized oligo- the required RNA phage polymerases. Six mice were examined in nucleotides were purchased from Life Technologies/Life Technolo- each group. For each mouse, one sagittal cryostat section (10 ␮m) was gies (Paisley, Renfrewshire, UK), ALZET 1007D osmotic mini- cut from intact kidney, which included cortex and outer and inner pumps and mice were purchased from Charles River UK (Margate, medulla. Sections were thaw-mounted onto 3-amino propyltriethox- 35 Kent, UK), and S[UTP] was purchased from Amersham Interna- ysilane–coated slides and stored at Ϫ80°C. 4% paraformaldehyde tional (Little Chalfont, Buck, UK). was used for fixation, followed by acetylation and prehybridization at 50°C for 2 h. Hybridization with 4 ϫ 106 c.p.m [35S]UTP-labeled Animal Treatments RNA probe per slide was performed at 50°C for 14 to 16 h and then The animal work was approved by the local ethical committee for followed by RNaseA treatment and washes with a maximum strin- the care of animals and was in accordance with the NIH Guidelines gency of 0.1xSSC at 60°C. This follows well-established methodol- for the Care and Use of Laboratory Animals. Eight-week-old male ogy that reflects findings that show that these conditions create the C57BL/6J mice (23.5 to 25 g) were segregated into ten groups (each high subsaturation/saturation riboprobe concentrations that provide n ϭ 6) and caged in pairs within their own group (Table 1). All mice specific radiolabeled probe hybridization that reflects the amount of had free access to normal diet (0.3% sodium) and water (with saline target RNA present. When quantitatively detected (film and dipped additionally available to adrenalectomized mice). The bilateral adre- emulsion autoradiography) this then allows relative quantitation for nalectomy operations were performed under gaseous anesthesia. An- sgk1 expression between slides processed together. After washes, imals were killed by terminal anesthesia. The ALZET 1007D osmotic slides were dehydrated and placed against ␤-Max Hyperfilms. Three mini-pumps (preloaded with treatments or vehicle) were implanted to five days of exposure gave a satisfactory range of autoradiographs subcutaneously to mice, generating groups having aldosterone infu- in the linear range of the films as judged by coincident exposure of the sions with various doses (50 ␮g/kg per d, 150 ␮g/kg per d, and 750 film to radioactive microscale standards for this
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