Lower mesodermal defects: A common cause of fetal and early neonatal death

Among the first 1,130 referrals to the Wisconsin Stillbirth Service Program 17 infants have been recognized to share phenotypic characteristics involving the genital, urinary, lower gastrointestinal, and axial skeletal systems. The pattern of abnormalities identified appears to be limited to structures sharing a common embryologic origin. These features, for the most part, are shown to be non-randomly associated. No clearly definable sub-groups within this population are demonstrable. The pattern of abnormalities is defined to include abnormalities of the following structures as pathogenetically primary features: lumbosacral vertebrae, kidneys, ureters, uterus/fallopian tubes, vagina, bladder, urethra, adrenals, gonads, anorectum, external genitalia, and umbilical arteries. An embryologic mechanism is proposed which explains this non-random association as arising secondary to disruption of structures derived from the lower portion of the primitive intra-embryonic mesoderm. The Lower Mesodermal Defects Sequence appears to be a rather common (and under-recognized) cause of stillbirth and immediate neonatal death. © 1994 Wiley-Liss, Inc.     

The growth hormone-insulin-like growth factor axis in kidney re-revisited.

The use of renal allotransplantation to treat ESRD in the US is limited by lack of organ availability. A possible solution is the transplantation of developing kidneys (metanephric allograft or xenografts). We have conducted studies that demonstrate the feasibility of such a strategy and have shown that IGF I may be useful to accelerate the growth and development of these transplanted organs. The rationale for the use of IGF I in this setting grew from a basic understanding of the role that the growth factor plays in kidney development. ARF in humans is the most costly kidney-related disease requiring hospitalization. Its incidence is increasing. Despite many advances in dialytic therapy, the mortality rate for patients with ARF has not changed in the last several decades. Strategies for treatment of ARF are directed toward supportive care to permit renal regeneration to occur. There exists a need for new therapeutic approaches that can speed recovery and reduce mortality. Although IGF I may not prove to be the 'magic bullet' for ARF, its proposal and testing as a potential therapeutic agent has provided a paradigm for the development of treatment modalities to accelerate renal regeneration based upon a basic understanding of the injury/repair process. The basis for development of a 'growth factor' therapy for ARF will probably evolve, at least in part, out of the testing and use of IGF I in rat models and in humans. The use of GH to treat ESRD was proposed shortly after its isolation and the demonstration of its action in increasing the rate of glomerular filtration. Later, it was discovered that the actions of GH on kidney are mediated by IGF I, and the means by which IGF I enhances glomerular filtration was elucidated. We have shown that humans with ESRD are not resistant to the actions of IGF I in enhancing the GFR, establishing the potential for use of IGF I as a pharmacological agent for ESRD. There is no effective drug therapy to enhance renal function in ESRD. Although much work remains to be done, and clearly caution is advised, our observations establish the potential for the use of IGF I as a therapeutic agent in this setting and justify continued study of IGF I as a medical therapy to delay the need for dialysis.     

Nephrogenesis accompanied by vascularisation in the mouse embryonic metanephros transplanted into the adult kidney for the creation of additional nephrons

SUMMARY: Metanephric kidneys of nude mice were transplanted on embryonic day 12 into an adult kidney of the same strain, and the growth of the implants was analysed histochemically to investigate the ontogenesis, structure and function of the newly developed additional nephrons. By using a light microscope, developing nephrons at various stages were observed in the implants growing in the host kidney 7 days after transplantation. Immature nephrons, comprising the nephrogenic zone, were intensely positive for proliferating cell nuclear antigen (PCNA) immunostaining, but were no longer present 14 days after transplantation. Vascular integration was observed between the host and implant tissues. Electron microscopic observation 14 days after transplantation showed that the afferent arterioles together with juxtaglomerular cells had entered the gtomeruli. All of the cell types were identified in the vascularised glomeruli with erythrocytes. the visceral epithelial cells had differentiated foot processes, whereas the endothelium of the glomerular tufts was rather thick in parts, and most of the epithelial and endothelial basement membranes were not fused. Several parts of the uriniferous tubules, including proximal and distal tubules, could be identified, and it was found that many of them had remained immature. Some proximal tubules with well-developed brush-border microvilli reabsorbed the horseradish peroxidase (HRP) injected into the host inferior vena cava, thus providing evidence of glomerular ultrafiltration in the vascularised implants perfused by the host. These findings indicate that the nephrogenesis in the implants followed a nearly normal developmental route and showed marked vascularisation, which promoted the organogenesis of the implanted metanephros and nephron function.     

The metanephros of the quail embryo. Developmental expression of carbonic anhydrase investigated by multiple approaches

The expression of carbonic anhydrase (CA) in the quail metanephros was investigated during embryonic development. The immunohistochemical localisation of the isoenzymes CAII and CAIII was compared with the distribution of enzyme activity visualised by a histochemical cobalt-precipitation procedure. The developmental profile of CA activity was also evaluated by means of a biochemical method. The occurrence of a moderate and diffuse CAII immunostaining from the first developmental appearance of the metanephros anlage testified to an early expression of carbonic anhydrase. This finding is discussed in relation to the involvement of the enzyme in the morphogenetic mechanisms leading to the establishment both of cell polarity and epithelial phenotype. CA expression in the renal sites that are positive in adults proved to be developmentally regulated. In the collecting duct system, enzyme activity could not be identified until the time of hatching. No CA was detected at any stage examined at the sites where, in adults, enzyme occurrence has previously been interpreted as a membrane-associated CA isoform. The differentiating renal tubules displayed no CAIII immunoreactivity. It can be argued that the bulk of the enzyme activity in the embryonic metanephros is due to the cytosolic isoenzyme CAII.     

Expression of transforming growth factor-β type II receptor mRNA in embryonic and adult rat kidney

Summary: The transforming growth factor-β (TGF-β) family of growth factors regulates cell proliferation, differentiation, extracellular matrix synthesis and angiogenesis in many developing tissues. Transforming growth factor-β1 was recently shown to affect the branching of ureteric epithelium and nephron formation in cultured rat metanephroi. As the TGF-β type II receptor is specific for the TGF-β family, the present study used in situ hybridization to localize mRNA for this receptor in metanephroi from Sprague-Dawley rat embryos. Transforming growth factor-β type II receptor mRNA was located in ureteric duct epithelium, undifferentiated mesenchymal cells in the nephrogenic zone, vesicles, comma-shaped bodies and S-shaped bodies. In some S-shaped bodies, TGF-β type II receptor mRNA was not expressed in the lower limb, which subsequently forms the renal corpuscle. Expression was not observed in capillary loop stage glomeruli and maturing glomeruli, or in proximal tubules and interstitial cells. In adult rat kidney, TGF-β type II receptor mRNA was expressed in cortical collecting ducts and distal tubules but not in glomeruli or proximal tubules. These findings demonstrate that the prominent expression of TGF-β type II receptor mRNA decreases as glomeruli and tubules develop. Expression then remains undetectable in adult glomeruli and proximal tubules. the developmentally-regulated expression of this receptor suggests a key role in glomerular and nephron development.     

Immunolocalization of fibroblast growth factor-1 and -2 in the embryonic rat kidney

Summary: Fibroblast growth factors (FGF) regulate cell proliferation, migration, differentiation and angiogenesis during morphogenesis in many different tissues. Recent evidence indicates that exogenous FGF-2 stimulates mesenchymal condensation in cultured rat metanephroi, a crucial epithelial-mesenchymal induction event in the developing nephron. the aim of the present investigation was to determine the in vivo distribution of FGF-1 and FGF-2 in developing rat metanephroi at embryonic days 14, 15, 16, 18 and 20. Avidin-biotin enhanced indirect immunohistochemistry was used to demonstrate that both FGF-1 and FGF-2 were co-localized in metanephroi at all ages studied. High levels of FGF-1 and FGF-2 were present in ureteric bud branches and in developing distal tubules. Fibroblast growth factor-1 and FGF-2 were colocalized in developing nephron elements, from vesicles to S-shaped bodies, and in the mesangium of capillary loop and maturing stage glomeruli. Both growth factors were present in the mesenchyme of the nephrogenic zone and in the interstitium of the developing cortex. However, immunostaining for FGF was not evident in mesenchymal condensates, endothelial cells, medullary interstitial cells, or in the thin undifferentiated epithelium of the immature loop of Henle. These findings indicate that the expression of both FGF-1 and FGF-2 is tightly regulated in the embryonic kidney and suggest a role for these molecules in kidney development.