To gain insight into the roles of cyclooxygenase (COX)-1 and -2 in human kidney, we analyzed their expressions and localization in adult and fetal normal kidney. Immunohistology showed expression of COX-1 in collecting duct cells, interstitial cells, endothelial cells, and smooth muscle cells of pre- and postglomerular vessels. Expression of COX-2 immunoreactive protein could be localized to endothelial and smooth muscle cells of arteries and veins and intraglomerularly in podocytes. In contrast to the rat, COX isoforms were not detected in the macula densa. These data were confirmed by in situ mRNA analysis using digoxigenin-labeled riboprobes. In fetal kidney, COX-1 was primarily expressed in podocytes and collecting duct cells. Expression levels of COX-1 in both cell types increased markedly from subcapsular to juxtamedullary cortex. Glomerular staining of COX-2 was detectable in podocytes only at the endstage of renal development. In summary, the localization of COX-2 suggests that this enzyme may be primarily involved in the regulation of renal perfusion and glomerular hemodynamics. The expression of COX-1 in podocytes of the fetal kidney and its absence in adult glomeruli suggests that this isoform might be involved in glomerulogenesis.

Renal prostaglandin (PG) synthesis is mediated by cyclooxygenase-1 and -2 (COX1 and COX2). After dehydration, the maintenance of normal renal function becomes particularly dependent upon PG synthesis. The present studies were designed to examine the potential link between medullary COX1 and COX2 expression in hypertonic stress. In response to water deprivation, COX2, but not COX1, mRNA levels increase significantly in the renal medulla, specifically in renal medullary interstitial cells (RMICs). Water deprivation also increases renal NF-κB-driven reporter expression in transgenic mice. NF-κB activity and COX2 expression could be induced in cultured RMICs with hypertonic sodium chloride and mannitol, but not urea. RMIC COX2 expression was also induced by driving NF-κB activation with a constitutively active IκB kinase α (IKKα). Conversely, introduction of a dominant-negative IκB mutant reduced COX2 expression after hypertonicity or IKKα induction. RMICs failed to survive hypertonicity when COX2 was downregulated using a COX2-selective antisense or blocked with the selective nonsteroidal anti-inflammatory drug (NSAID) SC58236, reagents that did not affect cell survival in isotonic media. In rabbits treated with SC58236, water deprivation induced apoptosis of medullary interstitial cells in the renal papilla. These results demonstrate that water deprivation and hypertonicity activate NF-κB. The consequent increase in COX2 expression favors RMIC survival in hypertonic conditions. Inhibition of RMIC COX2 could contribute to NSAID-induced papillary injury.

We found that MAGED2 mutations caused X-linked polyhydramnios with prematurity and a severe but transient form of antenatal Bartter's syndrome. MAGE-D2 is essential for fetal renal salt reabsorption, amniotic fluid homeostasis, and the maintenance of pregnancy. (Funded by the University of Groningen and others.).

BackgroundMutations in complement factor H (CFH), factor I (CFI), factor B (CFB), thrombomodulin (THBD), C3 and membrane cofactor protein (MCP), and autoantibodies against factor H (αFH) with or without a homozygous deletion in CFH-related protein 1 and 3 (∆CFHR1/3) predispose development of atypical hemolytic uremic syndrome (aHUS).MethodsDifferent mutations in genes encoding complement proteins in 45 pediatric aHUS patients were retrospectively linked with clinical features, treatment, and outcome.ResultsIn 47% of the study participants, potentially pathogenic genetic anomalies were found (5xCFH, 4xMCP, and 4xC3, 3xCFI, 2xCFB, 6xαFH, of which five had ∆CFHR1/3); four patients carried combined genetic defects or a mutation, together with αFH. In the majority (87%), disease onset was preceeded by a triggering event; in 25% of cases diarrhea was the presenting symptom. More than 50% had normal serum C3 levels at presentation. Relapses were seen in half of the patients, and there was renal graft failure in all except one case following transplant.ConclusionsPerforming adequate DNA analysis is essential for treatment and positive outcome in children with aHUS. The impact of intensive initial therapy and renal replacement therapy, as well as the high risk of recurrence of aHUS in renal transplant, warrants further understanding of the pathogenesis, which will lead to better treatment options.

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 ...