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Youfei Guan
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ABSTRACT: Peroxisome proliferator-activated receptors (PPAR) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Three PPAR isoforms, designated PPARalpha, -beta/delta, and -gamma, have been identified and attracted enormous attention as a result of the key role that these receptors play in regulating adipogenesis, lipid metabolism, insulin sensitivity, inflammation, and BP. Growing evidence points to a causative relationship between PPAR activity and the metabolic syndrome, including insulin resistance, glucose intolerance or type 2 diabetes, obesity, dyslipidemia, hypertension, atherosclerosis, and albuminuria. Importantly, both PPAR-alpha activators, such as the fibric acid class of hypolipidemic drugs, and PPAR-gamma agonists, including antidiabetic thiazolidinediones, have been proved to be effective for improving diverse aspects of the metabolic syndrome. All three PPAR isoforms seem to play important roles in the development of diabetic nephropathy in type 2 diabetes. Accumulating data suggesting that PPAR may serve as potential therapeutic targets for treating the metabolic syndrome and its related renal complications have begun to emerge. This article reviews the literature pertaining to the action, ligand selectivity, and physiologic role of PPAR. Particular emphasis is placed on their pathogenic roles in the metabolic syndrome and the therapeutic utility of PPAR modulators in the treatment of diabetic nephropathy.
Journal of the American Society of Nephrology 12/2004; 15(11):2801-15. · 9.66 Impact Factor
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ABSTRACT: Our aim is to investigate whether peroxisome proliferator-activator receptor-gamma (PPARgamma) expression was altered in human mesangial cells under inflammatory stress and whether PPARgamma could retard the inflammatory responses. Based on cultured human mesangial cell lines (HMCLs), PPARgamma expressions at protein and mRNA levels were observed by Western blot analysis and reverse transcriptase polymerase chain reaction. Informatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay. Our results demonstrated that PPARgamma protein expression was dramatically increased in HMCLs stimulated by IL-1beta (10 ng/mL). The levels of IL-6 and TNF-alpha in HMCL supernatants, protein, and mRNA expressions of PPARgamma in IL-1beta challenge cells were significantly increased more than those in untreated cells. Importantly, PPARgamma agonists troglitazone, rosiglitazone, and 15-deoxy-delta(12, 14)-prosglandin J2 significantly decreased the up expression of TNF-alpha and IL-6 in HMCL supernatants stimulated by IL-1beta. Furthermore, troglitazone downregulated TNF-alpha and IL-6 mRNA expression from IL-1beta challenge HMCLs. Our data suggest that PPARgamma plays an important role in mesangial cells responding to inflammatory stress. PPARgamma may prove to be a pharmacological target in glomerulonephritis.
Renal Failure 10/2004; 26(5):497-505. · 0.82 Impact Factor
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ABSTRACT: Genetic disruption of the mouse EP4 receptor results in perinatal lethality associated with persistent patent ductus areteriosus (PDA). To circumvent this, an EP4 allele amenable to conditional deletion using the Cre/loxP system was generated. The targeting construct was comprised of a floxed exon2 in tandem with the neomycin-resistance gene in intron 2, flanked by third 3' LoxP site. Mice homozygous for the targeted allele (EP4(lox+neo/lox+neo)), or following its Cre-mediated deletion (EP4(del/del)), also die within hours of birth with PDA. In contrast, mice homozygous for a partially recombined allele, retaining exon2 but lacking neo (EP4(flox/flox)), are viable and show no overt phenotype. Postnatal deletion of the floxed EP4 gene is efficiently achieved in the liver and kidney in a transgenic mouse expressing the inducible Mx1Cre recombinase. The EP4(flox) mouse should provide a useful reagent with which to examine the physiologic roles of the EP4 receptor.
genesis 10/2004; 40(1):7-14. · 2.53 Impact Factor
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André Schneider,
YaHua Zhang,
Mingzhi Zhang,
Wendell J Lu,
Reena Rao,
Xuefeng Fan,
Reyadh Redha,
Linda Davis,
Richard M Breyer,
Raymond Harris, YouFei Guan,
Matthew D Breyer
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ABSTRACT: Prostaglandin E2 (PGE2) plays an important role in many physiologic and pathophysiologic processes in the kidney. Multiple enzymes are involved in PGE2 biosynthesis, including phospholipases, cyclooxygenases (COX), and the PGE2 synthases (PGES). The present studies were aimed at determining the intrarenal localization of mPGES-1 and whether it is coexpressed with COX-1 or COX-2.
Rabbit mPGES-1 and COX-1 cDNAs were cloned using reverse transcription-polymerase chain reaction (RT-PCR) and screening a cDNA library. RNase protection assay and immunoblotting were used to examine mPGES-1 expression levels. In situ hybridization and immunostaining were used to determine the intrarenal localization of mPGES-1 and cyclooxygenases.
Rabbit mPGES-1 shares high sequence similarity to the human homolog. Nuclease protection studies showed that the kidney expresses among the highest level of mPGES-1 of any rabbit tissue. In situ hybridization showed COX-1 and mPGES-1 mRNA was highly expressed in renal medullary collecting ducts (MCD), and to a lesser extent in cortical collecting ducts (CCD). Fainter mPGES-1 expression was also observed in macula densa (MD) and medullary interstitial cells (RMICs), where COX-2 is highly expressed. Double-labeling studies (immunostaining plus in situ hybridization) and immunohistochemistry of mouse tissues confirmed that mPGES-1 predominantly colocalizes with COX-1 in distal convoluted tubule (DCT), CCD, and MCD, and is coexpressed with COX-2 at lower levels in MD and RMICs.
Together, these studies suggest mPGES-1 colocalizes with both COX-1 and COX-2 to mediate the biosynthesis of PGE2 in the kidney.
Kidney International 05/2004; 65(4):1205-13. · 6.61 Impact Factor
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ANDR|[Eacute]| SCHNEIDER,
YAHUA ZHANG,
MINGZHI ZHANG,
WENDELL J LU,
REENA RAO,
XUEFENG FAN,
REYADH REDHA,
LINDA DAVIS,
RICHARD M BREYER,
RAYMOND HARRIS, YOUFEI GUAN,
MATTHEW D BREYER
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ABSTRACT: Membrane-associated PGE synthase-1 (mPGES-1) is coexpressed with both COX-1 and COX-2 in the kidney.Background Prostaglandin E2 (PGE2) plays an important role in many physiologic and pathophysiologic processes in the kidney. Multiple enzymes are involved in PGE2 biosynthesis, including phospholipases, cyclooxygenases (COX), and the PGE2 synthases (PGES). The present studies were aimed at determining the intrarenal localization of mPGES-1 and whether it is coexpressed with COX-1 or COX-2.
Kidney International 03/2004; 65(4):1205-1213. · 6.61 Impact Factor
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Li-Jun Ma,
Su-Li Mao,
Kevin L Taylor,
Talerngsak Kanjanabuch, YouFei Guan,
YaHua Zhang,
Nancy J Brown,
Larry L Swift,
Owen P McGuinness,
David H Wasserman,
Douglas E Vaughan,
Agnes B Fogo
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ABSTRACT: Increased plasminogen activator inhibitor 1 (PAI-1) has been linked to not only thrombosis and fibrosis but also to obesity and insulin resistance. Increased PAI-1 levels have been presumed to be consequent to obesity. We investigated the interrelationships of PAI-1, obesity, and insulin resistance in a high-fat/high-carbohydrate (HF) diet-induced obesity model in wild-type (WT) and PAI-1-deficient mice (PAI-1(-/-)). Obesity and insulin resistance developing in WT mice on an HF diet were completely prevented in mice lacking PAI-1. PAI-1(-/-) mice on an HF diet had increased resting metabolic rates and total energy expenditure compared with WT mice, along with a marked increase in uncoupling protein 3 mRNA expression in skeletal muscle, likely mechanisms contributing to the prevention of obesity. In addition, insulin sensitivity was enhanced significantly in PAI-1(-/-) mice on an HF diet, as shown by euglycemic-hyperinsulinemic clamp studies. Peroxisome proliferator-activated receptor (PPAR)-gamma and adiponectin mRNA, key control molecules in lipid metabolism and insulin sensitivity, were maintained in response to an HF diet in white adipose tissue in PAI-1(-/-) mice, contrasting with downregulation in WT mice. This maintenance of PPAR-gamma and adiponectin may also contribute to the observed maintenance of body weight and insulin sensitivity in PAI-1(-/-) mice. Treatment in WT mice on an HF diet with the angiotensin type 1 receptor antagonist to downregulate PAI-1 indeed inhibited PAI-1 increases and ameliorated diet-induced obesity, hyperglycemia, and hyperinsulinemia. PAI-1 deficiency also enhanced basal and insulin-stimulated glucose uptake in adipose cells in vitro. Our data suggest that PAI-1 may not merely increase in response to obesity and insulin resistance, but may have a direct causal role in obesity and insulin resistance. Inhibition of PAI-1 might provide a novel anti-obesity and anti-insulin resistance treatment.
Diabetes 03/2004; 53(2):336-46. · 8.29 Impact Factor
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ABSTRACT: Prostaglandin E(2) (PGE(2)) plays an important role in genitourinary function. Multiple enzymes are involved in its biosynthesis. Here we report the genomic structure and tissue-selective expression of cytosolic PGE(2) synthase (cPGES) in genitourinary tissues. Full-length mouse cPGES cDNA was cloned by reverse transcript-polymerase chain reaction (RT-PCR) and 5'- and 3'-rapid amplification of cDNA ends (RACE). Analysis of a cPGES cDNA with partially sequenced cPGES genomic clones and bioinformatic databases demonstrates that the murine cPGES gene spans approximately 22 kb and consists of eight exons. The cPGES gene promoter is GC-rich and contains many SP1 sites but lacks an obvious TATA box motif. RNase protection assay revealed constitutive expression of cPGES was greatest in the testis with lower levels in the ovary, kidney, bladder and uterus. In situ hybridization studies demonstrated that cPGES mRNA was most highly expressed in the epithelial cells of seminiferous tubules in the testis. In the female reproductive tissues, cPGES was mainly localized in ovarian primary and secondary follicles and oviductal epithelial cells with less expression in uterine endometrium. In the kidney cPGES expression was diffusely expressed. In urinary bladder, cPGES expression was restricted to the transitional epithelial cells. This expression pattern is consistent with an important role for cPGES-mediated PGE(2) in urogenital tissue function.
Biochimica et Biophysica Acta 11/2003; 1634(1-2):15-23. · 4.66 Impact Factor
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ABSTRACT: Macula densa (MD) cells express COX-2 and COX-2-derived PGs appear to signal the release of renin from the renal juxtaglomerular apparatus, especially during volume depletion. However, the synthetic machinery and identity of the specific prostanoid released from intact MD cells remains uncertain. In the present studies, a novel biosensor tool was engineered to directly determine whether MD cells release PGE2 in response to low luminal NaCl concentration ([NaCl]L). HEK293 cells were transfected with the Ca2+-coupled E-prostanoid receptor EP1 (HEK/EP1) and loaded with fura-2. HEK/EP1 cells produced a significant elevation in intracellular [Ca2+] ([Ca2+]i) by 29.6 +/- 12.8 nM (n = 6) when positioned at the basolateral surface of isolated perfused MD cells and [NaCl]L was reduced from 150 mM to zero. HEK/EP1 [Ca2+]i responses were observed mainly in preparations from rabbits on a low-salt diet and were completely inhibited by either a selective COX-2 inhibitor or an EP1 antagonist, and also by 100 microM luminal furosemide. Also, 20-mM graduated reductions in [NaCl]L between 80 and 0 mM caused step-by-step increases in HEK/EP1 [Ca2+]i. Low-salt diet greatly increased the expression of both COX-2 and microsome-associated PGE synthase (mPGES) in the MD. These studies provide the first direct evidence that intact MD cells synthesize and release PGE2 during reduced luminal salt content and suggest that this response is important in the control of renin release and renal vascular resistance during salt deprivation.
Journal of Clinical Investigation 08/2003; 112(1):76-82. · 15.39 Impact Factor
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ABSTRACT: PGF(2alpha) is one of the major prostanoids produced by the kidney. The cellular effects of PGF(2alpha) are mediated by a G protein-coupled transmembrane receptor designated the FP receptor. Both in situ hybridization and beta-galactosidase knocked into the endogenous FP locus were used to determine the cellular distribution of the mouse FP receptor. Specific labeling was detected in the kidney, ovary, and uterus. Abundant FP expression in ovarian follicles and uterus is consistent with previous reports of failed parturition in FP-/- mice. In the kidney, coexpression of the mFP mRNA with the thiazide-sensitive cotransporter defined its expression in the distal convoluted tubule (DCT). FP receptor was also present in aquaporin-2-positive cortical collecting ducts (CCD). No FP mRNA was detected in glomeruli, proximal tubules, or thick ascending limbs. Intrarenal expression of the FP receptor in the DCT and CCD suggests an important role for the FP receptor regulating water and solute transport in these segments of the nephron.
American journal of physiology. Renal physiology 07/2003; 284(6):F1164-70. · 3.68 Impact Factor
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ABSTRACT: The Cre/loxP transgenic system may be used to achieve temporally and/or spatially regulated gene deletion. The Mx1Cre mouse expresses Cre recombinase under control of the IFN-inducible Mx1 promoter. Mx1Cre mice were crossed with a reporter strain (ROSA26tm1Sor) in which beta-galactosidase activity is expressed only after Cre-mediated recombination to determine the cellular pattern of Cre-mediated genetic recombination in the kidney and other tissues. Widespread recombination was observed in vascular endothelium as well as in the liver and spleen. Recombination was restricted to subsets of stromal cells in uterus, duodenum, colon, aorta, and kidney. In the cortex, chi-galactosidase activity was detected in a subset of tubules and all glomerular cells, including endothelium, mesangium, and podocytes. No chi-galactosidase activity was detected in proximal tubules. Costaining of kidneys with segment-specific markers demonstrated induction of chi-galactosidase activity in collecting duct, with sporadic labeling of the thick ascending limb but no significant labeling of distal convoluted tubules. We conclude that Mx1-driven gene recombination is spatially as well as temporally restricted. The Mx1Cre transgene should prove a useful reagent to achieve temporally regulated recombination in endothelial, glomerular, and distal renal epithelia in mice.
American journal of physiology. Renal physiology 03/2003; 284(2):F411-7. · 3.68 Impact Factor
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ABSTRACT: Activators of peroxisome proliferator activated receptor gamma (PPARgamma) have been shown to modulate chemokine expression in isolated monocytes/macrophages (M/M) and to exert anti-inflammatory effects in some models of experimental inflammatory diseases. We evaluated the effects of different forms of PPARgamma activators in a model of experimental glomerulonephritis (GN) in rats.
GN was induced in rats by application of an anti-thymocyte antibody (ATS). Nephritic rats were treated with two synthetic PPARgamma ligands of the thiazolidinedione (TZD) group, troglitazone (200 mg/kg/day) and ciglitazone (100 mg/kg/day), and with a natural ligand 15d-PGJ2 (1.5 mg/day). Twenty-four hours after induction of the GN, the glomerular mRNA expression of the chemokine monocyte chemoattractant protein-1 (MCP-1) and the cognate chemokine receptor CCR-2 were examined by Northern blotting and RT-PCR. The glomerular M/M infiltration was determined by immunohistology. The activation of the transcription factors PPARgamma, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) in glomeruli was analyzed by electrophoretic mobility shift assay.
Induction of GN up-regulated glomerular nuclear protein binding of NF-kappaB and AP-1. Treatment of nephritic rats with troglitazone and ciglitazone augmented nuclear PPARgamma and AP-1 DNA binding but did not affect NF-kappaB binding. TZD enhanced glomerular MCP-1 expression and increased glomerular M/M recruitment. In contrast, 15d-PGJ2 attenuated NF-kappaB activation and did not affect AP-1 activity or MCP-1 expression.
Our data show that PPARgamma activators of the TZD group, but not 15d-PGJ2, enhance MCP-1 expression and M/M infiltration in the induction phase of experimental GN. The results demonstrate that TZD and 15d-PGJ2 may exert different effects in the immune response in experimental GN. Our study underscores the need to critically evaluate whether PPARgamma ligands will have beneficial or possibly deleterious effects in GN.
Kidney International 09/2002; 62(2):455-64. · 6.61 Impact Factor
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ABSTRACT: Effects of different PPAR-agonists on MCP-1 expression and monocyte recruitment in experimental glomerulonephritis.Background Activators of peroxisome proliferator activated receptor (PPAR) have been shown to modulate chemokine expression in isolated monocytes/macrophages (M/M) and to exert anti-inflammatory effects in some models of experimental inflammatory diseases. We evaluated the effects of different forms of PPAR activators in a model of experimental glomerulonephritis (GN) in rats.
Kidney International 07/2002; 62(2):455-464. · 6.61 Impact Factor
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ABSTRACT: Prostaglandin E2 (PGE2) has multiple physiologic roles mediated by G protein coupled receptors designated E-prostanoid, or "EP" receptors. Evidence supports an important role for the EP2 receptor in regulating fertility, vascular tone and renal function.
The full-length rabbit EP2 receptor cDNA was cloned. The encoded polypeptide contains 361 amino acid residues with seven hydrophobic domains. COS-1 cells expressing the cloned rabbit EP2 exhibited specific [3H]PGE2 binding with a Kd of 19.1 +/- 1.7 nM. [3H]PGE2 was displaced by unlabeled ligands in the following order: PGE2>PGD2=PGF2alpha=iloprost. Binding of [3H]PGE2 was also displaced by EP receptor subtype selective agonists with a rank order of affinity consistent with the EP2 receptor (butaprost>AH13205>misoprostol>sulprostone). Butaprost free acid produced a concentration-dependent increase in cAMP accumulation in rabbit EP2 transfected COS-1 cells with a half-maximal effective concentration of 480 nM. RNase protection assay revealed high expression in the ileum, spleen, and liver with lower expression in the kidney, lung, heart, uterus, adrenal gland and skeletal muscle. In situ hybridization localized EP2 mRNA to the uterine endometrium, but showed no distinct localization in the kidney. EP2 mRNA expression along the nephron was determined by RT-PCR and its expression was present in glomeruli, MCD, tDL and CCD. In cultured cells EP2 receptor was not detected in collecting ducts but was detected in renal interstitial cells and vascular smooth muscle cells. EP2 mRNA was also detected in arteries, veins, and preglomerular vessels of the kidney.
EP2 expression pattern is consistent with the known functional roles for cAMP coupled PGE2 effects in reproductive and vascular tissues and renal interstitial cells. It remains uncertain whether it is also expressed in renal tubules.
BMC Pharmacology 06/2002; 2:14.
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ABSTRACT: We found that peroxisome proliferator-activated receptor-gamma (PPARgamma) mRNA was reduced by 77% in glomeruli of diabetic mice. Because mesangial cells play an important role in diabetic nephropathy, we examined regulation of type I collagen expression by PPARgamma and transforming growth factor-beta(1) (TGF-beta(1)) in mouse mesangial cells in the presence of 6 and 25 mM glucose. Mesangial cells contained functionally active PPARgamma. Exposure to 25 mM glucose resulted in reduced PPARgamma expression and transcriptional activity, accompanied by increased type I collagen expression. Restoration of PPARgamma activity to normal levels in cells cultured in 25 mM glucose, by transfection with a PPARgamma expression construct and treatment with the PPARgamma agonist troglitazone, returned type I collagen levels toward normal values. Activation of PPARgamma by troglitazone also decreased type I collagen mRNA and blocked TGF-beta(1)-mediated upregulation of type I collagen mRNA and protein. Moreover, PPARgamma activation suppressed basal and activated TGF-beta(1) responses in mesangial cells. This action was blocked by transfection of cells with a dominant-negative PPARgamma construct. In summary, PPARgamma suppresses the increased type I collagen mRNA and protein expression mediated by TGF-beta(1) in mesangial cells.
American journal of physiology. Renal physiology 05/2002; 282(4):F639-48. · 3.68 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are transcription factors that belong to the nuclear hormone receptor superfamily. PPAR has three isoforms designated PPARalpha, PPARbeta/delta and PPARgamma. Although all three isoforms share similar protein sequence and structure, they differ in tissue distribution, ligand selectivity and biological actions. As ligand-activated transcription factors, PPARs participate in a broad spectrum of biological processes, including cell differentiation, energy balance, lipid metabolism, insulin sensitivity, bone formation, inflammation and tissue remodeling. PPARalpha is the molecular target of the hypolipidemic fibrates including benzafibrate and clofibrate. In general, PPARalpha is expressed in tissues with high mitochondrial and beta-oxidation activity corresponding to its role in regulating lipid metabolism. In contrast, PPARbeta/delta is ubiquitously expressed and has been suggested to be involved in bone formation, oocyte implantation and lipid catabolism. PPARbeta/delta ligands have been found to effectively improve lipid profile and insulin resistance. PPARgamma is a key player in adipogenesis and plays an important role in diverse cellular processes such as cell cycle regulation, cell differentiation and insulin sensitivity. Synthetic PPARgamma ligands, including thiazolidinediones and non-thiazolidinedione compounds, have been shown to increase insulin sensitivity and improve hyperglycemia in insulin resistance and noninsulin dependent diabetes mellitus. The biological effects of PPARs indicate that both agonists and antagonists for PPARs may provide new therapeutic options in a variety of human diseases. (c) 2002 Prous Science. All rights reserved.
Drug News & Perspectives 05/2002; 15(3):147-154. · 2.21 Impact Factor
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genesis 03/2002; 32(2):134-7. · 2.53 Impact Factor
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genesis 02/2002; 32(2):134 - 137. · 2.53 Impact Factor
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Advances in experimental medicine and biology 02/2002; 507:321-6. · 1.09 Impact Factor
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ABSTRACT: Abstract
Background
Prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) has multiple physiologic roles mediated by G protein coupled receptors designated E-prostanoid, or "EP" receptors. Evidence supports an important role for the EP<sub>2</sub> receptor in regulating fertility, vascular tone and renal function.
Results
The full-length rabbit EP<sub>2</sub> receptor cDNA was cloned. The encoded polypeptide contains 361 amino acid residues with seven hydrophobic domains. COS-1 cells expressing the cloned rabbit EP<sub>2</sub> exhibited specific [<sup>3</sup>H]PGE<sub>2</sub> binding with a K<sub>d</sub> of 19.1± 1.7 nM. [<sup>3</sup>H]PGE<sub>2</sub> was displaced by unlabeled ligands in the following order: PGE<sub>2</sub>>>PGD<sub>2</sub>=PGF<sub>2α</sub>=iloprost. Binding of [<sup>3</sup>H]PGE<sub>2</sub> was also displaced by EP receptor subtype selective agonists with a rank order of affinity consistent with the EP2 receptor (butaprost>AH13205>misoprostol>sulprostone). Butaprost free acid produced a concentration-dependent increase in cAMP accumulation in rabbit EP<sub>2</sub> transfected COS-1 cells with a half-maximal effective concentration of 480 nM. RNase protection assay revealed high expression in the ileum, spleen, and liver with lower expression in the kidney, lung, heart, uterus, adrenal gland and skeletal muscle. In situ hybridization localized EP<sub>2</sub> mRNA to the uterine endometrium, but showed no distinct localization in the kidney. EP2 mRNA expression along the nephron was determined by RT-PCR and its expression was present in glomeruli, MCD, tDL and CCD. In cultured cells EP2 receptor was not detected in collecting ducts but was detected in renal interstitial cells and vascular smooth muscle cells. EP2 mRNA was also detected in arteries, veins, and preglomerular vessels of the kidney.
Conclusion
EP2 expression pattern is consistent with the known functional roles for cAMP coupled PGE<sub>2</sub> effects in reproductive and vascular tissues and renal interstitial cells. It remains uncertain whether it is also expressed in renal tubules.
BMC Pharmacology. 01/2002;
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ABSTRACT: Prostaglandins (PGs) are ubiquitous lipid mediators derived from cyclooxygenase
metabolism of arachidonic acid that exert a broad range of physiologic activities,
including modulation of inflammation, ovulation1,
2 and arterial
blood pressure3,
4. PGE2, a chief cyclooxygenase
product, modulates blood pressure and fertility, although the specific G protein−coupled
receptors5,
6 mediating these effects remain poorly defined.
To evaluate the physiologic role of the PGE2 EP2 receptor
subtype, we created mice with targeted disruption of this gene (EP2
−/−). EP2
−/− mice
develop normally but produce small litters and have slightly elevated baseline
systolic blood pressure. In EP2
−/− mice,
the characteristic hypotensive effect of intravenous PGE2 infusion
was absent; PGE2 infusion instead produced hypertension. When fed
a diet high in salt, the EP2
−/− mice
developed profound systolic hypertension, whereas wild−type mice showed
no change in systolic blood pressure. Analysis of wild−type and EP
2
−/− mice on day 5 of pregnancy indicated
that the reduced litter size of EP2
−/−
mice is due to a pre−implantation defect. This reduction of implanted
embryos could be accounted for by impaired ovulation and dramatic reductions
in fertilization observed on day 2 of pregnancy. These data demonstrate that
the EP2 receptor mediates arterial dilatation, salt−sensitive
hypertension, and also plays an essential part in female fertility.
Nature Medicine 01/1999; 5(2):217-220. · 22.46 Impact Factor
