Cyclooxygenase-2–selective inhibitors impair glomerulogenesis and renal cortical development

Abstract

Cyclooxygenase-2-selective inhibitors impair glomerulogenglandins in renal development. These renal abnormaliesis and renal cortical development.ties range from oliguria to renal dysgenesis and have Background. Antenatal exposure to nonsteroidal anti-inflambeen seen particularly when NSAIDs were administered matory drugs (NSAIDs) has been associated with renal dysgenbefore the 32nd week of gestation [1, 2]. Similar findings esis in humans.were observed in offspring of rhesus monkeys treated Methods. These studies characterized cyclooxygenase-2 (COX-2) versus COX-1-selective inhibition on nephrogenesis with indomethacin during gestation [3]. Avner and coin the rodent using histomorphometry, immunohistology, and workers showed that prostaglandin E 1 (PGE 1 ) is necesin situ hybridization. sary for maximal growth and differentiation of meta-Results. Administration of a COX-2-selective inhibitor nephroi in culture [4]. Taken together, these data suggest (SC58236), started during pregnancy until weaning, signifian important role for cyclooxygenase (COX)-mediated cantly impaired development of the renal cortex and reduced glomerular diameter in both mice and rats. An identical phenoprostaglandin formation in renal development.type was demonstrated in COX-2 Ϫ/Ϫ mice. In contrast to its Two isoforms of COX are known to exist. COX-1 is effects on the developing kidney, a COX-2 inhibitor had no expressed constitutively and considered a housekeeping effect on glomerular volume in adult mice. This effect was gene, having important roles in the maintenance of epispecific for COX-2 because maternal administration of a COXthelial integrity. COX-2 was identified as an immediate 1-selective inhibitor (SC58560) did not affect renal development despite significantly inhibiting gastric mucosal prostaglan-early-response gene, up-regulated in fibroblasts treated din E 2 (PGE 2 ) synthesis in pups. The expression of COX-2 with tumor-promoting phorbol esters [5]. COX-2 is not immunoreactivity peaked in the first postnatal week and was constitutively expressed in many tissues and is only oblocalized to S-shaped bodies and the macula densa in the cortex. served after they are exposed to cytokines and growth Treatment with a COX-2 inhibitor during this period (from factors. However, COX-2 is expressed constitutively in postnatal day 0 to day 21) severely reduced glomerular diamefetal and adult kidney in all species examined [6][7][8][9]. Gene ter, whereas treatment limited to pregnancy did not affect glomerular size.knockout studies show that COX-1 disruption does not Conclusion. These data demonstrate an important role for interfere with normal renal development [10]. In con-COX-2 activity in nephrogenesis in the rodent, and define a trast, COX-2-deficient mice exhibit renal dysgenesis asspecific time period of susceptibility to these effects. sociated with hypoplastic glomeruli [11, 12]. These structural renal abnormalities in COX-2 null mice have not been quantitatively defined. Furthermore, the effect of Reports of renal dysgenesis in ...

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

“…The greatest effect of the COX-2 inhibition, however, was seen postnatally in mice and rats at a stage comparable to 24 to 32 weeks' human gestation. The immunoreactivity of COX-2 in these animals peaked in the first two weeks after birth and thereafter decreased (19). Inactivation of the COX-2 gene in mice from birth to six weeks of age resulted in normal prenatal and early postnatal renal development.…”

Effect of Drugs on Renal Development

“…These drugs inhibit the (renal) cyclooxygenase system, and a well known side effect of treatment in premature neonates is anuria or oliguria during the course of treatment, which occurs less often during treatment with ibuprofen (25). Because a normalfunctioning cyclooxygenase system is essential for nephrogenesis, it can be expected that these drugs not only influence short-term renal function, but also impair nephron formation (21,26,27). Indeed, harmful renal effects have been shown of acetylsalicyclic acid, another prostaglandin synthetase inhibitor (28).…”

Colorectal Adenomas

“…Rare cases of acute renal failure have also been reported (105). These effects highlight the pivotal role of COX-2-dependent prostaglandins in normal renal development and maintenance (106,107).…”