Deficiency of COX-2 results in progressive and specific renal architectural disruption and functional deterioration beginning in the final phases of nephrogenesis. Tissue-specific and time-dependent expression of COX-2 appears necessary for normal postnatal renal development and the maintenance of normal renal architecture and function.

To determine whether low oxygen is a stimulus for endothelial cell differentiation and vascular development in the kidney, we examined the effect of low oxygen on rat metanephric organ culture, a model known to recapitulate nephrogenesis in the absence of vessels. After 6 days in culture in standard (20% O2) or low oxygen (1-3% O2) conditions, metanephric kidney growth and morphology were assessed by DNA measurement, and light and electron microscopy. DNA content was higher in 3% O2-treated explants (2.5 +/- 0.17 microgram/kidney, n = 9) than in 20% O2 explants (1.5 +/- 0.09 microgram/kidney, n = 9), P < 0.05. Low oxygen induced proliferation of tubular epithelial cells, resulting in enhanced number of tubules of similar size. Endothelial cells forming capillaries were localized in 3% O2 explants by light and electron microscopy and by immunocytochemistry using endothelial cell markers. Flt-1, Flk-1, and ACE-containing cells were detected in 3% O2-treated explants, whereas 20% O2 explants were virtually negative. VEGF mRNA levels were 10-fold higher in 3% O2-treated explants than in 20% O2-treated explants. Addition of anti-VEGF antibodies to 3% O2-treated explants prevented low oxygen-induced growth and endothelial cell differentiation and proliferation. Our data indicate that low oxygen stimulates growth by cell proliferation and induces tubulogenesis, endothelial cell differentiation, and vasculogenesis in metanephric kidneys in culture. Upregulation of VEGF expression by low oxygen and prevention of low oxygen-induced tubulogenesis and vasculogenesis by anti-VEGF antibodies indicate that these changes were mediated by VEGF. These data suggest that low oxygen is the stimulus to initiate renal vascularization.

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Angiotensin II (ANG II) and its receptors, AT1 and AT2, may modulate kidney development. To define the temporal and spatial distribution of AT1 and AT2 receptors and their mRNAs during nephrogenesis, fetal, newborn, and adult rat kidneys were studied using reverse transcription-polymerase chain reaction and radioligand binding autoradiography. AT1 expression was minimal at embryonic day 14 (E14), highly expressed at E20, and persisted into adulthood. Conversely, AT2 expression was easily detected from E14 through postnatal day 7 but was undetectable by postnatal day 28. At E14, 76% of the receptors were AT2, 24% were AT1, and both were found in the undifferentiated mesenchyme. By E17, AT1 comprised 40% of the receptors and localized to mature nephron segments, whereas AT2 remained within both condensed mesenchyme and differentiating epithelia. The dissociation constants for AT1 and AT2 were 0.45 +/- 0.09 nM and 0.73 +/- 0.15 nM, respectively, at E17, similar to adult values. By E20, AT1 and AT2 colocalized to the outer medullary stripe, deep nephrons, medullary rays, and blood vessels, while AT2 continued to predominate in the actively differentiating cortex. The presence of both subtypes of receptors capable of binding ANG II during early nephrogenesis and the time-dependent and structure-specific regulation of receptor localization confirm a regulated developmental program for receptor expression and suggest important roles for AT1 and AT2 in renal morphogenesis.

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Objective To assess depression in children with chronic kidney disease (CKD) and to determine associations with patient characteristics, intellectual and educational levels, and health related quality of life (HRQoL). Study design Subjects aged 6–17 years from the Chronic Kidney Disease in Children cohort study completed the Children’s Depression Inventory (CDI), Wechsler’s Abbreviated Scales of Intelligence, Wechsler Individual Achievement Test-II-Abbreviated, and the Pediatric Inventory of Quality of Life Core Scales 4.0. Regression analyses determined associations of CDI score and depression status with subject characteristics, intellectual and educational levels, and HRQoL. A joint linear mixed model and Weibull model were used to determine the effects of CDI score on longitudinal changes in glomerular filtration rate (GFR) and time to renal replacement therapy. Results 344 subjects completed the CDI. Eighteen (5%) had elevated depressive symptoms and another 7 (2%) were being treated for depression. In adjusted analyses, maternal education beyond high school was associated with 5% lower CDI scores (estimate 0.95; 95% CI 0.92, 0.99). Depression status was associated with lower IQ (99 versus 88, P= 0.053), lower achievement (95 versus 77.5, P<0.05), and lower HRQoL by parent and child reports (effect estimates −15.48; 95% CI −28.71, −2.24 and −18.39; 95% CI −27.81, −8.96, respectively). CDI score was not related to change in GFR. Conclusion Children with depression had lower psychoeducational skills and worse HRQoL. Identifying and treating depression should be evaluated as a means to improve the academic performance and HRQoL of children with CKD.

Kidney morphogenesis is accomplished by the coordinated interaction of molecular signals that culminate in the production of an organ that is architecturally and functionally ready for extrauterine, free life. In humans, nephrogenesis is completed before birth. However the kidney continues to mature both from a functional and anatomical point of view. Throughout its development, the kidney is susceptible to a variety of injurious agents. This brief review considers the basic mechanisms of kidney organogenesis and functional maturation. To illustrate some concepts, the renal alterations caused by interference with a normal regulatory system, the renin-angiotensin system is discussed.

Renal juxtaglomerular (JG) cells are specialized myoepithelioid cells located in the afferent arteriole at the entrance to the glomerulus. Their main function and distinctive feature is the synthesis and release of renin, the key hormone-enzyme of the renin-angiotensin system that regulates arterial blood pressure. Despite their relevance to health and disease, not much is known about factors that confer and/or maintain JG cell identity. To identify genes uniquely expressed in JG cells, we used a cell culture model and RNA differential display. JG cells cultured for 2 days express renin and renin mRNA, but after 10 days in culture they no longer contain or release renin and renin mRNA is reduced 700-fold. We report one cDNA differentially expressed in the 2-day JG cell culture that detects a 2.6-kb mRNA expressed at higher levels in newborn than adult kidney. Screening a 2-day culture JG cell cDNA library yielded clones representing differentially spliced transcripts. These cDNAs encode one unique protein (Zis) containing zinc fingers and domains characteristic of splicing factors and RNA binding proteins. Northern blot analysis confirmed Zis mRNA expression in differentiated JG cells, and identified an additional unique 1.5-kb transcript. The Zis transcripts are developmentally regulated in kidney and a number of other organs. The features of the Zis protein and its organ distribution suggest a possible role in regulation of transcription and/or splicing, both important steps for controlling developmentally expressed genes.