Postnatal development and progression of renal dysplasia in cyclooxygenase-2 null mice

Norwood, Victoria F.; Morham, Scott G.; Smithies, Oliver

doi:10.1046/j.1523-1755.2000.00413.x

Cited by 108 publications

(96 citation statements)

References 12 publications

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“…1 In addition, several studies have reported that mice lacking COX2 develop immature glomeruli and poorly differentiated tubuli. [2][3][4] As reported in an interesting study performed by Yang et al, 4 the proteinuria, renal structural damage, and development of hypertension are significantly influenced by genetic background and gender in 3 congenic lines of COX2 knockout mice. However, it was unknown whether the reduction in COX2 activity during renal development leads to a decrease in nephron number and whether this potential reduction in 3-to 4-mo-old rats nϭ6 n ϭ7 n ϭ6 n ϭ7…”

Section: Discussionmentioning

confidence: 90%

“…[2][3][4] These effects have also been found after the administration of a COX2-specific inhibitor during the nephrogenic period in mice. 5 Furthermore, it is well known that COX2 appears in the developing rodent metanephros starting at embryonic day 16, and it is upregulated in the kidney during the first 2 weeks of life.…”

mentioning

confidence: 76%

“…21 We cannot discard that the increment in arterial pressure is secondary to other effects elicited by COX2 inhibition, because it has been reported that the lack of COX2 in mice leads to abnormalities in cortical tubuli. [2][3][4] In addition, the higher blood pressure found in COX2 Inh np -treated rats may also be partly secondary to an enhanced response to stress 22 and to the lower weight gain during the first weeks of life. 8,9 As shown in Table 1, the mean increment in body weight during the first 3 weeks of life was greater in litters of vehicle-treated than in litters of COX2 Inh np -treated rats.…”

Section: Discussionmentioning

confidence: 99%

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Hypertension and Sex Differences in the Age-Related Renal Changes When Cyclooxygenase-2 Activity Is Reduced During Nephrogenesis

et al. 2009

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Abstract-Several studies have proposed that cyclooxygenase-2 (COX2) is involved in the regulation of nephrogenesis and that an impaired nephrogenesis may induce the development of hypertension. This study was designed to test the hypothesis that the decrease of COX2 activity leads to a reduction in nephron number, an increase in arterial pressure, and age-dependent renal alterations that are greater in male than in female rats. Arterial pressure was measured from the first to the 16th month of life in rats treated with vehicle or a COX2 inhibitor during the nephrogenic period. Stereological and histological evaluations and renal function studies were performed at different ages. Arterial pressure increased (14%; PϽ0.05) and nephron number decreased (17%; PϽ0.05) to similar levels in male and female COX2-treated rats. However, glomerular filtration rate (31%) and renal plasma flow (25%) decreased (PϽ0.05) in male but not in female COX2-treated rats. A greater (PϽ0.05) age-dependent elevation in glomerular hypertrophy was also found in male COX2-treated rats compared with their female littermates. Glomerulosclerosis and tubulointerstitial damage in renal cortex and medulla were also significantly enhanced in male but not in female aged COX2-treated rats.Our results demonstrate that the decrease in COX2 activity during renal development leads to a reduction in nephron number and to an elevation in arterial pressure that are similar in males and females. However, the consequent age-dependent deterioration of the renal structure and renal function is only significantly enhanced in male rats. Key Words: fetal programming Ⅲ glomerulosclerosis Ⅲ renal fibrosis Ⅲ aging Ⅲ proteinuria Ⅲ cyclooxygenases Ⅲ prostaglandins T he importance of cyclooxygenase-2 (COX2)-derived metabolites in the regulation of renal morphogenesis is supported by studies showing that the use of nonsteroidal anti-inflammatory drugs as tocolytics is related to renal abnormalities and renal failure in the neonate 1 and that COX2-deficient mice show a thin nephrogenic cortex and immature glomeruli and tubuli. 2-4 These effects have also been found after the administration of a COX2-specific inhibitor during the nephrogenic period in mice. 5 Furthermore, it is well known that COX2 appears in the developing rodent metanephros starting at embryonic day 16, and it is upregulated in the kidney during the first 2 weeks of life. 6,7 The link among a suboptimal nephron endowment, hypertension, and an age-dependent development of renal damage has been shown in many studies, 8 -11 but nowadays it is unknown whether the reduction in COX2 activity during the nephrogenic period leads to a lower nephron number, hypertension, and a progressive deterioration of the renal structure and function.The objective of this study was to evaluate the effects of COX2 inhibition during the nephrogenic period (COX2 Inh np ) on nephron number and on the age-dependent changes in arterial pressure, renal structure, and renal function. Because recent works of our group have reported s...

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Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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Hypertension and Sex Differences in the Age-Related Renal Changes When Cyclooxygenase-2 Activity Is Reduced During Nephrogenesis

et al. 2009

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“…These facts, together with its inducible property during inflammation and other pathogenesis (4 -6), agree well with the proposal that mPGES-1 represents a target for the treatment of various inflammatory diseases that will spare important physiological systems in which other PGs are involved (44). However, implementation of this concept will still require caution, because besides its proinflammatory functions PGE 2 exerts homeostatic and antiinflammatory effects in several organs, such as the gastrointestinal tract (69,70), lung (71), and kidney (72). It also remains to be elucidated whether other PGES enzymes exhibit redundant or specific functions in particular situations in vivo.…”

Section: Discussionmentioning

confidence: 99%

Reduced Pain Hypersensitivity and Inflammation in Mice Lacking Microsomal Prostaglandin E Synthase-1

Kamei

Yamakawa

Takegoshi

et al. 2004

Journal of Biological Chemistry

264

245

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We examined the in vivo role of membrane-bound prostaglandin E synthase (mPGES)-1, a terminal enzyme in the PGE 2 -biosynthetic pathway, using mPGES-1 knockout (KO) mice. Comparison of PGES activity in the membrane fraction of tissues from mPGES-1 KO and wild-type (WT) mice indicated that mPGES-1 accounted for the majority of lipopolysaccharide (LPS)-inducible PGES in WT mice. LPS-stimulated production of PGE 2 , but not other PGs, was impaired markedly in mPGES-1-null macrophages, although a low level of cyclooxygenase-2-dependent PGE 2 production still remained. Pain nociception, as assessed by the acetic acid writhing response, was reduced significantly in KO mice relative to WT mice. This phenotype was particularly evident when these mice were primed with LPS, where the stretching behavior and the peritoneal PGE 2 level of KO mice were far less than those of WT mice. Formation of inflammatory granulation tissue and attendant angiogenesis in the dorsum induced by subcutaneous implantation of a cotton thread were reduced significantly in KO mice compared with WT mice. Moreover, collagen antibody-induced arthritis, a model for human rheumatoid arthritis, was milder in KO mice than in WT mice. Collectively, our present results provide unequivocal evidence that mPGES-1 contributes to the formation of PGE 2 involved in pain hypersensitivity and inflammation.

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“…Thereafter progressive organ-specific renal dysplasia was observed, first affecting the last generation of formed nephrons, later the entire kidney. Over time cystic degeneration of renal tissue was seen with loss of renal function without rise in blood pressure (20).…”

Section: Intrauterine Cox-1/2 Inhibition Renal Morphogenesismentioning

confidence: 99%

The adverse renal effects of prostaglandin-synthesis inhibition in the fetus and the newborn

Drukker

2002

Paediatrics &Amp; Child Health

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OBJECTIVES:To summarize experimental animal data and to provide a limited literature review on the adverse renal effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the developing fetus and the maturing newborn. DATA: The experimental data were obtained from anesthetized, ventilated, six-to eight-day-old rabbits that received an intravenous bolus of either acetylsalicylic acid (ASA), ibuprofen (IBU) or indomethacin (INDO). In one set of experiments, ASA was also tested in 12-week-old (young adult) rabbits. Renal function was monitored with inulin and para-aminohippuric acid clearances measuring glomerular filtration rate (GFR) and renal blood flow. The renal vascular resistance was calculated. All three nonspecific cyclo-oxygenase-1 or -2 (COX-1/2) inhibitors caused remarkably similar reversible, oliguric, acute renal failure (ARF). In young adult animals, the side effects were attenuated. The underlying pathophysiology is related to the carefully maintained low GFR of the fetus and the newborn, dependent on a delicate interplay between vasoconstriction (angiotensin II) and vasodilation (prostaglandins [PGs]). When PG-synthesis is inhibited, the vasoconstriction is relatively unopposed, causing ARF. LITERATURE REVIEW: The renal effects of fetal exposure to NSAIDs are discussed, as are new insights into the role of COX-1/2 for a normal nephrogenesis. COX-nil or COX-inhibited animals have long lasting renal structural injury. Fetuses exposed in utero to significant amounts of NSAIDs have at birth various degrees of renal insufficiency and structural renal defects with a very high mortality. CONCLUSIONS: All NSAIDs, both specific and nonspecific COX inhibitors, have renal side effects in the immediate postnatal period and should, therefore, be given with the utmost caution. NSAIDs given during pregnancy for the prevention of toxemia, polyhydramnios and premature labour may affect fetal renal function and structure. In animal experiments, IBU was not less nephrotoxic than INDO, as suggested recently by human premature neonates.

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Postnatal development and progression of renal dysplasia in cyclooxygenase-2 null mice

Cited by 108 publications

References 12 publications

Hypertension and Sex Differences in the Age-Related Renal Changes When Cyclooxygenase-2 Activity Is Reduced During Nephrogenesis

Hypertension and Sex Differences in the Age-Related Renal Changes When Cyclooxygenase-2 Activity Is Reduced During Nephrogenesis

Reduced Pain Hypersensitivity and Inflammation in Mice Lacking Microsomal Prostaglandin E Synthase-1

The adverse renal effects of prostaglandin-synthesis inhibition in the fetus and the newborn

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