Expression of peroxisome proliferator-activated receptors in urinary tract of rabbits and humans

Guan, Youfei; Zhang, Yahua; Davis, Linda S.; Breyer, Matthew D.

doi:10.1152/ajprenal.1997.273.6.f1013

Cited by 154 publications

(172 citation statements)

References 38 publications

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“…Because electrolyte and water metabolism are largely maintained at the renal level, it is reasonable to speculate that renal mechanisms will play a major role in TZD-induced fluid retention. Within the kidney, PPAR␥ is highly expressed in the renal medullary CD, with lower expression levels in glomeruli, proximal tubules, and microvasculature, as demonstrated by both RT-PCR and microdissection and by in situ hybridization techniques (17,18,28). This distribution pattern suggests the possibility that local activation of PPAR␥ in the CD may stimulate sodium reabsorption and account for the fluid retention.…”

Section: Discussionmentioning

confidence: 90%

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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.

313

269

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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: Discussionmentioning

confidence: 90%

“…Within the kidney, PPAR␥ is predominantly expressed in the inner medulla and in the inner medullary collecting duct (CD) (17,18), a critical site for the control of fluid metabolism. Therefore, we hypothesize that activation of PPAR␥ in the distal nephron may serve as the primary mechanism responsible for TZD-induced fluid retention.…”

mentioning

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.

313

269

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“…Total RNA was isolated, and Northern blot analyses were performed as described (13). The PPAR-␦ probe was a 471-bp PPAR-␦ cDNA fragment generated by RT-PCR using human liver mRNA (Clontech) with primers 5Ј-AGC-AGC-CTC-TTC-CTC-AAC-GAC-CAG-3Ј and 5Ј-GGT-CTC-GGT-TTC-GGT-CTT-CTT-GAT-3Ј (20).…”

Section: Methodsmentioning

confidence: 99%

The 15-lipoxygenase-1 product 13- S -hydroxyoctadecadienoic acid down-regulates PPAR-δ to induce apoptosis in colorectal cancer cells

Shureiqi

Jiang

Zuo

et al. 2003

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

215

192

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“…However, the exact site of NO production is unknown, because PPAR␥ receptors are present in many renal cells that express NOS and produce NO. [87][88][89][90] Finally, reactive oxygen species production by the kidney and their role in scavenging NO have recently received a great deal of attention. 91 Superoxide plays a quintessential role in determining NO bioavailability and thus its effect.…”

Section: Other Regulators Of Nos Activitymentioning

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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Expression of peroxisome proliferator-activated receptors in urinary tract of rabbits and humans

Cited by 154 publications

References 38 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

The 15-lipoxygenase-1 product 13- S -hydroxyoctadecadienoic acid down-regulates PPAR-δ to induce apoptosis in colorectal cancer cells

Recent Advances in the Regulation of Nitric Oxide in the Kidney

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