Collecting duct-specific knockout of endothelin-1 alters vasopressin regulation of urine osmolality

Ge, Yuqiang; Ahn, Dowahn; Stricklett, Peter K.; Hughes, Alisa K.; Yanagisawa, Masashi; Verbalis, Joseph G.; Kohan, Donald E.

doi:10.1152/ajprenal.00432.2004

Cited by 98 publications

(96 citation statements)

References 48 publications

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“…The PPAR␥ floxed mice, containing two loxP sites inserted into introns 1 and 2 of the PPAR␥ gene flanking the critical exon 2, were generated by homologous recombination in ES cells (19). AQP2-Cre transgenic mice expressing Cre under the control of mouse AQP2 promoter (20) were used to produce a CD-specific disruption of the PPAR␥ gene. To assess CreTag activity in vivo, AQP2-Cre mice were bred with reporter mice (ROSA26-YFP).…”

Section: Resultsmentioning

confidence: 99%

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Collecting duct-specific deletion of peroxisome proliferator-activated receptor γ blocks thiazolidinedione-induced fluid retention

Zhang

Kohan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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315

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The peroxisome proliferator-activated receptor subtype ␥ (PPAR␥) ligands, namely the synthetic insulin-sensitizing thiazolidinedione (TZD) compounds, have demonstrated great potential in the treatment of type II diabetes. However, their clinical applicability is limited by a common and serious side effect of edema. To address the mechanism of TZD-induced edema, we generated mice with collecting duct (CD)-specific disruption of the PPAR␥ gene. We found that mice with CD knockout of this receptor were resistant to the rosiglitazone-(RGZ) induced increases in body weight and plasma volume expansion found in control mice expressing PPAR␥ in the CD. RGZ reduced urinary sodium excretion in control and not in conditional knockout mice. Furthermore, RGZ stimulated sodium transport in primary cultures of CD cells expressing PPAR␥ and not in cells lacking this receptor. These findings demonstrate a PPAR␥-dependent pathway in regulation of sodium transport in the CD that underlies TZD-induced fluid retention.roziglitazone ͉ Cre recombinase ͉ Evans blue technique T hiazolidinediones (TZDs), synthetic insulin-sensitizing drugs that include troglitazone, pioglitazone, and rosiglitazone (RGZ), are highly effective in the treatment of type II diabetes. TZDs are believed to mediate their antidiabetic effect via activation of peroxisome proliferator-activated receptor ␥ (PPAR␥) (1). In addition to lowering blood glucose, these drugs also benefit cardiovascular parameters, such as blood pressure and endothelial function (2, 3). However, fluid retention, presented as rapid weight gain, and peripheral and pulmonary edema have emerged as the most common and serious side effects of TZDs (4-6). Global awareness of this side effect has increased as a result of the growing number of reported cases. In a recent issue of Circulation (7), the American Heart Association and American Diabetes Association jointly issued a Consensus Statement commenting on the safety of TZD as related to edema. The mechanisms of fluid retention in patients treated with TZDs are poorly understood and may involve a number of factors, including reduction of urinary sodium excretion (8), alteration of endothelial permeability (9), increased sympathetic nervous system activity (10), or altered interstitial ion transport (11). To evaluate the relative contributions of these individual mechanisms, tissue-or cell-type-specific approaches are needed in carefully designed studies.PPARs are a group of zinc finger-containing transcription factors, representing a family of the nuclear hormone receptor gene superfamily. To date, three subtypes of PPARs encoded by different genes have been described from several species: PPAR␣, -␤͞␦, and -␥ (12, 13). They share a high degree of similarity in their overall amino acid sequences, particularly in the DNA-binding domain (14). The three isoforms of the PPARs heterodimerize with retinoid X receptor, bind to the same peroxisome proliferatorresponsive element in the promoter regions of their target genes, and modulate gene transcripti...

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Section: Resultsmentioning

confidence: 99%

“…The genotype of the AQP2-Cre mice was performed as described (20). Genotyping the PPAR␥ gene involved the use of primers PPAR␥ F1 (5Ј-CTCCAATGTTCTCAAACTTAC-3Ј) and PPAR␥ R1 (5Ј-GAT GAGTCATGTAAGTTGACC-3Ј), which yielded a 225-bp band from the wild-type allele and a 275-bp band from the floxed allele.…”

Section: Methodsmentioning

confidence: 99%

Collecting duct-specific deletion of peroxisome proliferator-activated receptor γ blocks thiazolidinedione-induced fluid retention

Zhang

Kohan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

315

269

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“…New technology that allows deletion or expression of a particular gene in specific tissues in the kidney is an important scientific advance. Over the past few years, various animal models have been developed using such technology 13,[93][94][95] that provide new means of studying the physiological actions of a single NOS isoform in a single cell type at a specific point in time in vivo.…”

Section: Perspectivesmentioning

confidence: 99%

Recent Advances in the Regulation of Nitric Oxide in the Kidney

Herrera

Garvin

2005

Hypertension

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Abstract-Nitric oxide (NO) plays important roles in the regulation of renal function and the long-term control of blood pressure. New roles of NO have been proposed recently in diabetes, nephrotoxicity, and pregnancy. NO derived from all 3 NOS isoforms contributes to the overall regulation of kidney function, and recent advances in our understanding of their regulation have been made lately. In this regard, substrate and cofactor availability play important roles in regulating nitric oxide synthase (NOS) activity not only by limiting enzyme activity but also by influencing the coupling of NOS with its cofactors, tetrahydrobiopterin and NADPH. Protein-protein interactions are now recognized to be important negative and positive regulators of NOS. Phosphorylation is another component of the mechanism whereby NOS is activated or deactivated. Increased NOS expression can also influence enzyme activity; however, the degree of expression does not always correlate with enzyme activity because increased NO levels can result in inhibition of NOS. Finally, other potential regulators of NOS such as endogenous L-arginine analogs may also be important. In this article, we summarize recent advances in the regulation of activity and expression of the NOS isoforms within the kidney. renal function and long-term regulation of blood pressure. [1][2][3][4] This is best evidenced by the fact that inhibiting intrarenal NO production increased blood pressure. 5 In addition, reduced NO has been identified as a common denominator of many hypertensive models. 6 -9 The effects of NO on blood pressure via actions in the kidney occur through multiple mechanisms. These include increasing renal blood flow caused by vasodilatation, 10 increasing glomerular filtration, 11 inhibiting sodium transport along the nephron, 12-14 and regulating release of renin. 15 NO produced by each of the 3 nitric oxide synthases (NOS), NOS 1, NOS 2, and NOS 3, reportedly contributes to the regulation of renal function. Inhibition of NOS activity within the kidney is known to lead to sodium retention and hypertension. This review addresses recent advances in our understanding of the role played by renal NO in various physiological and pathophysiological conditions, as well as how NO production is regulated. Roles for Renal NOHistorically, NO produced by the kidney has been thought of primarily as a factor that regulates urinary volume and sodium excretion. The physiological effects of NO can be mediated via changes in renal hemodynamics and/or salt and water absorption by the nephron. NO reduces renal vascular tone in part by dilating the afferent arteriole. 16 It also increases glomerular filtration rate. 11 NO modulates renin secretion by the juxtaglomerular apparatus 15 and tubuloglomerular feedback. 3 Finally, NO regulates transport in various nephron segments as reviewed recently by Ortiz and Garvin. 12 More recently it has been recognized that in a number of pathophysiological conditions, the actions of NO on renal hemodynamics and/or nephron transport are ...

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“…Indeed, both hormones have been implicated in cardiac and renal fibrosis, glomerular damage, and proteinuric disease (10,23,24). In the kidney, ET-1 has effects on renal hemodynamics (25,26), sodium and water homeostasis (27)(28)(29)(30)(31), and acid-base balance (32). These same processes are also influenced by aldosterone.…”

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confidence: 99%

Aldosterone Modulates Steroid Receptor Binding to the Endothelin-1 Gene (edn1)

Stow

Gumz

Lynch

et al. 2009

Journal of Biological Chemistry

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Aldosterone and endothelin-1 (ET-1) act on collecting duct cells of the kidney and are important regulators of renal sodium transport and cardiovascular physiology. We recently identified the ET-1 gene (edn1) as a novel aldosterone-induced transcript. However, aldosterone action on edn1 has not been characterized at the present time. In this report, we show that aldosterone stimulated edn1 mRNA in acutely isolated rat inner medullary collecting duct cells ex vivo and ET-1 peptide in rat inner medulla in vivo. Aldosterone induction of edn1 mRNA occurred in cortical, outer medullary, and inner medullary collecting duct cells in vitro. Inspection of the edn1 promoter revealed two putative hormone response elements. Levels of heterogeneous nuclear RNA synthesis demonstrated that edn1 mRNA stimulation occurred at the level of transcription. RNA knockdowns corroborated pharmacological studies and demonstrated both mineralocorticoid receptor and glucocorticoid receptor participated in this response. Aldosterone resulted in dose-dependent nuclear translocation and binding of mineralocorticoid receptor and glucocorticoid receptor to the edn1 hormone response elements. Hormone receptors mediated the association of chromatin remodeling complexes, histone modification, and RNA polymerase II at the edn1 promoter. Direct interaction between aldosterone and ET-1 has important implications for renal and cardiovascular function.The steroid hormone aldosterone is critical for sodium homeostasis and blood pressure control. Aldosterone works by modulating the fine regulation of sodium reabsorption in the distal nephron and collecting duct of the kidney. Classic aldosterone action is mediated through the mineralocorticoid receptor (MR), 3 a member of the nuclear receptor family of proteins that function as ligand-dependent transcription factors (1). MR acts on cells of the distal nephron and collecting duct to stimulate transcription of genes involved in transepithelial sodium transport, including the epithelial sodium channel ␣ subunit (scnn1a, ␣ENaC), the sodium, potassium-ATPase ␣1 subunit (atp1a1), and the serum-and glucocorticoid-regulated kinase-1 (sgk1) (2). The increase in expression of genes involved in sodium transport results in net sodium reabsorption followed by in increase in extracellular fluid volume and a consequent increase in blood pressure. Indeed, MR antagonists such as spironolactone and eplerenone are used clinically as diuretic and anti-hypertensive agents (3). The mechanism of MR action is consistent with a classic steroid receptor mechanism (4). Prior to activation MR resides in the cytosol. Ligand binding induces a conformational change that releases chaperone proteins and reveals a nuclear localization signal. Nuclear MR binds directly to DNA at hormone response elements (HREs) in target genes to modulate their transcription. A typical HRE for MR consists of two receptor binding half-sites with the consensus sequence 5Ј-TGTTCT-3Ј, arranged as an inverted palindrome (1, 5). These HREs facilitate binding of...

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Collecting duct-specific knockout of endothelin-1 alters vasopressin regulation of urine osmolality

Cited by 98 publications

References 48 publications

Collecting duct-specific deletion of peroxisome proliferator-activated receptor γ blocks thiazolidinedione-induced fluid retention

Collecting duct-specific deletion of peroxisome proliferator-activated receptor γ blocks thiazolidinedione-induced fluid retention

Recent Advances in the Regulation of Nitric Oxide in the Kidney

Aldosterone Modulates Steroid Receptor Binding to the Endothelin-1 Gene (edn1)

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