Aldosterone-Induced Serum and Glucocorticoid-Induced Kinase 1 Expression Is Accompanied by Nedd4-2 Phosphorylation and Increased Na+ Transport in Cortical Collecting Duct Cells

Flores, Sandra Y.; Loffing‐Cueni, Dominique; Kamynina, Elena; Daidié, Dorothée; Gerbex, Carole; Chabanel, Sting; Loffing, Johannes; Staub, Olivier

doi:10.1681/asn.2004100828

Cited by 83 publications

(69 citation statements)

References 42 publications

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“…Previous studies on rat (24) and human (36) kidneys indicated that Nedd4-2 is expressed in several nephron portions. To confirm these observations for mouse kidneys, we performed RT-PCR experiments on microdissected tubules from mice (n ϭ 3) that were on the standard-Na ϩ diet (0.8% Na ϩ ).…”

Section: Detection Of Nedd4-2 Mrna In Microdissected Nephron Portionsmentioning

confidence: 97%

“…Serial cryosections (4 m thick) were incubated with one of the following primary antibodies: Affinity-purified rabbit anti-mouse Nedd4-2 (A26; [24]) diluted 1:500, affinity-purified rabbit anti-mouse Nedd4-2 (A27 [33]) diluted 1:200, rabbit anti-rat ␣-ENaC diluted 1:500 (29), rabbit anti-rat ␤-ENaC diluted 1:500 (29), mouse anti-bovine H-ATPase diluted 1:4 (34), or mouse anti-chicken calbindin D28K diluted 1:20,000 (Swant, Bellinzona, Switzerland). The binding sites of the primary antibodies were revealed by Cy3-conjugated goat anti-rabbit IgG (Jackson ImmunoResearch Laboratories, West Grove, PA) and FITC-conjugated goat anti-mouse Ig (Jackson ImmunoResearch Laboratories) diluted 1:1000 and 1:40, respectively.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…For further confirmation of qualitative ratings about Nedd4-2 immunofluorescent intensities, micrographs of the stained cryosections were taken and analyzed by determining the mean pixel intensities (MPI) in at least three randomly selected CCD profiles of each animal. MPI were determined with National Institutes of Health Imaging software, normalized to the background fluorescence in nuclei of PT, and expressed in arbitrary units as described previously (24) Cell Culture…”

Section: Evaluation Of Immunofluorescencementioning

confidence: 99%

“…Little is known about the in vivo regulation of Nedd4-2. Previous studies addressed the shortterm effect of aldosterone on Nedd4-2 in the CD but did not examine the more chronic effects of altered dietary Na ϩ intake (24). In this study, we used two Nedd4-2-specific affinitypurified Nedd4-2 antisera, directed against different epitopes within Nedd4-2, to provide a comprehensive analysis of the distribution and regulation by dietary Na ϩ intake of Nedd4-2 along the nephron.…”

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confidence: 99%

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Dietary Sodium Intake Regulates the Ubiquitin-Protein Ligase Nedd4-2 in the Renal Collecting System

Loffing‐Cueni¹,

Flores²,

Sauter³

et al. 2006

Journal of the American Society of Nephrology

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The activity of the epithelial sodium (Na ؉ ) channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN) needs to be tightly regulated to match urinary Na ؉ excretion with dietary Na ؉ intake. The ubiquitin-protein ligase Nedd4-2, which in vitro interacts with ENaC subunits and reduces ENaC cell surface abundance and activity by ubiquitylation of the channel, may participate in the control of ENaC. This study confirms in vivo by reverse-transcriptase-PCR that Nedd4-2 is expressed throughout the nephron and is detectable by immunoblotting in kidney extracts. By immunohistochemistry, Nedd4-2 was found to be strongly expressed in the ASDN, with low staining intensity in the late distal convoluted tubule and early connecting tubule (where apical ENaC is high) and gradually increasing detection levels toward the collecting duct (CD; where apical ENaC is low). Compared with high-Na ؉ diet (5% Na ؉ ), 2 wk of low-Na ؉ diet (0.01% Na ؉ ) drastically reduces Nedd4-2 immunostaining and increases apical ENaC abundance in ASDN. Reduced Nedd4-2 immunostaining is not dependent on increased apical Na ؉ entry in the CD, because it is similarly observed in mice with intact and with suppressed apical ENaC activity in the CD. Consistent with a role of mineralocorticoid hormones in the long-term regulation of Nedd4-2, 5-d treatment of cultured CD (mpkCCD cl4 ) cells with 1 M aldosterone leads to reduction of Nedd4-2 protein expression. It is concluded that Nedd4-2 abundance is regulated by Na ؉ diet, by a mechanism that likely involves aldosterone. This regulation may contribute to adaptation of apical ENaC activity to altered Na ؉ intake.

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Section: Detection Of Nedd4-2 Mrna In Microdissected Nephron Portionsmentioning

confidence: 97%

Section: Immunohistochemistrymentioning

confidence: 99%

Section: Evaluation Of Immunofluorescencementioning

confidence: 99%

mentioning

confidence: 99%

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Dietary Sodium Intake Regulates the Ubiquitin-Protein Ligase Nedd4-2 in the Renal Collecting System

Loffing‐Cueni¹,

Flores²,

Sauter³

et al. 2006

Journal of the American Society of Nephrology

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“…38 Activation of sgk1 through the PI3-kinase pathway may serve to link aldosterone-activated pathways to other modulators of sodium transport such as insulin. 28 Aldosterone increases PI3-kinase activity, perhaps through increased expression of the monomeric G-protein k-ras.…”

Section: Epithelial Aldosterone-induced Proteinsmentioning

confidence: 99%

Mechanisms of Mineralocorticoid Action

Fuller¹,

Young²

2005

Hypertension

275

169

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Abstract-Sodium transport in epithelial tissues is regulated by the physiological mineralocorticoid aldosterone. The response to aldosterone is mediated by the mineralocorticoid receptor (MR), for which the crystal structure of the ligand-binding domain has recently been established. The classical mode of action for this receptor involves the regulation of gene transcription. Several genes have now been shown to be regulated by aldosterone in epithelial tissues. Of these, the best characterized is serum-and glucocorticoid-regulated kinase, which increases sodium influx through the epithelial sodium channel. Turnover of these channels in the cell membrane is mediated by Nedd4 -2, a ubiquitin protein ligase; serum-and glucocorticoid-regulated kinase interacts with and phosphorylates Nedd4 -2, thereby rendering it unable to bind the sodium channels. Key Words: aldosterone Ⅲ sodium channels Ⅲ fibrosis T he isolation of aldosterone just over 50 years ago established it as the primary physiological mineralocorticoid. 1 Sodium transport, and hence salt balance, is regulated by a number of mechanisms; however, aldosterone has a critical role. Aldosterone exerts its effects on the distal nephron (and colon) as the last point of sodium reabsorption; it is thus the final arbiter. 2,3 The importance of aldosterone in the maintenance of sodium homeostasis is seen in a series of monogenetic causes of hypertension, 2 in Conn's syndrome, and in disorders in which mineralocorticoid action is compromised with consequent, life-threatening salt losses. 3 Although other pathophysiological consequences of aldosterone excess were identified by Selye 4 over 60 years ago, their significance has only recently been appreciated. Evidence from the Randomized ALdactone Evaluation Study (RALES) and EPlerenone neuroHormonal Efficacy and SUrvival Study (EPHESUS) trials of beneficial effects of mineralocorticoid antagonist therapy on morbidity and mortality in cardiac failure has focused attention beyond the kidney to effects of mineralocorticoids more broadly in the cardiovascular system. 5 Although an understanding of the molecular basis of aldosterone action has tended to lag behind advances in the biology of other steroid hormones, the last decade has seen significant advances toward an understanding of the mechanisms of mineralocorticoid action. The primary mediator of the response to aldosterone is the mineralocorticoid receptor (MR), the ligand-binding domain (LBD) of which has been recently crystallized. 6 -8 Although the MR primarily acts as a transcription factor, recent evidence suggests that it may also mediate nongenomic (or nonnuclear) activation of second messenger pathways. In addition, there is a growing body of evidence that some actions of aldosterone may involve a receptor other than the MR. The cellular and molecular mediators, including proteins induced by aldosterone, have been characterized in sodium transporting epithelia; however, the critical molecular events in the vasculature remain to be determined. In this brief r...

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HECT Ubiquitin‐Protein Ligases in Human Disease

Scheffner

Staub

2007

Protein Degradation Series

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Aldosterone-Induced Serum and Glucocorticoid-Induced Kinase 1 Expression Is Accompanied by Nedd4-2 Phosphorylation and Increased Na+ Transport in Cortical Collecting Duct Cells

Cited by 83 publications

References 42 publications

Dietary Sodium Intake Regulates the Ubiquitin-Protein Ligase Nedd4-2 in the Renal Collecting System

Dietary Sodium Intake Regulates the Ubiquitin-Protein Ligase Nedd4-2 in the Renal Collecting System

Mechanisms of Mineralocorticoid Action

HECT Ubiquitin‐Protein Ligases in Human Disease

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