Prostacyclin-Deficient Mice Develop Ischemic Renal Disorders, Including Nephrosclerosis and Renal Infarction

Yokoyama, Chieko; Yabuki, Tomoko; Shimonishi, Manabu; Wada, M.; Hatae, Toshihisa; Ohkawara, Susumu; Takeda, Junji; Kinoshita, Taroh; Okabe, Masaru; Tanabe, Tadashi

doi:10.1161/01.cir.0000034733.93020.bc

Cited by 110 publications

(88 citation statements)

References 33 publications

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“…However, chronic renal pathology was found in adult COX-1 Ͼ COX-2 mice (Fig. 4) with low PGI 2 biosynthesis, which is somewhat reminiscent of the renal phenotype reported in PGIS-deficient mice (39). These findings with COX-1 Ͼ COX-2 mice agree with the notion of PGI 2 biosynthesis coupled to COX-2 and provide additional evidence for a COX-2-derived PGI 2 role in renal homeostasis.…”

Section: Discussionsupporting

confidence: 75%

“…The altered PG biosynthesis in COX-1 Ͼ COX-2 mice (with COX-2 deletion) might allow a relative rediversion of knocked-in COX-1-derived PGH 2 toward PGE 2 formation if coupling to PGI 2 synthase (PGIS) is affected. Evidence for such rediversion to PGE 2 is apparent in PGIS-deficient mice (39).…”

Section: Discussionmentioning

confidence: 96%

“…These findings with COX-1 Ͼ COX-2 mice agree with the notion of PGI 2 biosynthesis coupled to COX-2 and provide additional evidence for a COX-2-derived PGI 2 role in renal homeostasis. However, no kidney phenotype was reported in PGI 2 receptor-deficient mice, and the PGI 2 receptor agonist, beraprost, cannot mitigate kidney damage in PGIS-deficient mice (39), implying that COX-2-derived PGI 2 might function to maintain kidney homeostasis through pathways other than the PGI 2 receptor (39,40).…”

Section: Discussionmentioning

confidence: 99%

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Targeted Cyclooxygenase Gene (Ptgs) Exchange Reveals Discriminant Isoform Functionality

Fan

Hui

et al. 2007

Journal of Biological Chemistry

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The prostaglandin G/H synthase enzymes, commonly termed COX-1 and COX-2, differ markedly in their responses to regulatory stimuli and their tissue expression patterns. COX-1 is the dominant source of "housekeeping" prostaglandins, whereas COX-2 synthesizes prostaglandins of relevance to pain, inflammation, and mitogenesis. Despite these distinctions, the two enzymes are remarkably conserved, and their subcellular distributions overlap considerably. To address the functional interchangeability of the two isozymes, mice in which COX-1 is expressed under COX-2 regulatory elements were created by a gene targeting "knock-in" strategy. In macrophages from these mice, COX-1 was shown to be lipopolysaccharide-inducible in a manner analogous to COX-2 in wild-type macrophages. However, COX-1 failed to substitute effectively for COX-2 in lipopolysaccharide-induced prostaglandin E 2 synthesis at low concentrations of substrate and in the metabolism of the endocannabinoid 2-arachidonylglycerol. The marked depression of the major urinary metabolite of prostacyclin in COX-2 null mice was only partially rescued by COX-1 knock-in, whereas the main urinary metabolite of prostaglandin E 2 was rescued totally. Replacement with COX-1 partially rescued the impact of COX-2 deletion on reproductive function. The renal pathology consequent to COX-2 deletion was delayed but not prevented, whereas the corresponding peritonitis was unaltered. Insertion of COX-1 under the regulatory sequences that drive COX-2 expression indicated that COX-1 can substitute for some COX-2 actions and rescue only some of the consequences of gene disruption. Manipulation of COX-2 also revealed a preference for coupling with distinct downstream prostaglandin synthases in vivo. These mice will provide a valuable reagent with which to elucidate the distinct roles of the COX enzymes in mammalian biology.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Targeted Cyclooxygenase Gene (Ptgs) Exchange Reveals Discriminant Isoform Functionality

Fan

Hui

et al. 2007

Journal of Biological Chemistry

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“…This may result from shunting of endoperoxides toward other prostanoid synthetic pathways. This phenomenon has been observed in other circumstances when prostanoid synthetic enzymes are genetically deleted (39) or pharmacologically inhibited (40). Because PGI 2 and PGE 2 have some redundant functions (8), this increase in PGI 2 generation might act as a compensatory mechanism to ameliorate the physiologic consequences of mPGES1 deficiency.…”

Section: Discussionmentioning

confidence: 60%

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

François

Facemire

Kumar

et al. 2007

Journal of the American Society of Nephrology

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Prostaglandin E 2 (PGE 2 ) is one of the most ubiquitous prostanoids in the kidney, where it may influence a wide range of physiologic functions. PGE 2 is generated through enzymatic metabolism of prostanoid endoperoxides by specific PGE synthases (PGES). Several putative PGES have been identified and cloned, including the membrane-associated, inducible microsomal PGES1 (mPGES1), which is expressed in the kidney. To evaluate the physiologic role of mPGES1 in the kidney, mice with targeted disruption of mPges1 gene were studied, with a focus on responses where PGE 2 has been implicated, including urinary concentration, regulation of blood pressure, and response to a loop diuretic. The absence of mPGES1 was associated with a 50% decrease in basal excretion of PGE 2 in urine (P < 0.001). In female but not male mPGES1-deficient mice, there was a reciprocal increase in basal excretion of other prostanoids. Nonetheless, urinary osmolalities were similar in mPges1 ؉/؉ and mPges1 ؊/؊ mice at baseline and after 12 h of water deprivation. Likewise, there were no differences in blood pressure between mPGES1-deficient and wild-type mice on control or high-or low-salt diets. The furosemide-induced increase in urinary PGE 2 excretion that was seen in wild-type mice was attenuated in mPGES1-deficient mice. However, furosemide-associated diuresis was reduced only in male, not female, mPGES1-deficient mice. Stimulation of renin by furosemide was not affected by mPGES1 deficiency. These data suggest that mPGES1 contributes to basal synthesis of PGE 2 , but there are other pathways that lead to renal PGE 2 synthesis. Moreover, there are significant gender differences in physiologic contributions of mPGES1 to control kidney function.

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“…Female PGIS-null mice in a C57BL/6 strain (Yokoyama et al 2002) were used in our study. PGIS C/K animals have no abnormal phenotype.…”

Section: Animalsmentioning

confidence: 99%

Increased bone mass in adult prostacyclin-deficient mice

Nakalekha

Yokoyama

Miura³

et al. 2009

Journal of Endocrinology

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Prostaglandins (PGs) are key regulatory factors that affect bone metabolism. Prostaglandin E 2 (PGE 2 ) regulates bone resorption and bone formation. Prostacyclin (PGI 2 ) is one of the major products derived from arachidonic acid by the action of cyclooxygenase and PGI 2 synthase (PGIS). Unlike PGE 2 , there are few reports about the role of PGI 2 in bone regulation. Therefore, we investigated the potential effect of PGI 2 on bone metabolism. We used PGIS knockout (PGIS K/K ), PGIS heterozygous (PGIS C/K

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Prostacyclin-Deficient Mice Develop Ischemic Renal Disorders, Including Nephrosclerosis and Renal Infarction

Cited by 110 publications

References 33 publications

Targeted Cyclooxygenase Gene (Ptgs) Exchange Reveals Discriminant Isoform Functionality

Targeted Cyclooxygenase Gene (Ptgs) Exchange Reveals Discriminant Isoform Functionality

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

Increased bone mass in adult prostacyclin-deficient mice

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