Atrial natriuretic peptide and renal disease.
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Biomedical subjects
Publications and source records attributed to A S Woolf.
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The changes in plasma atrial natriuretic peptide (ANP) were studied in four adult patients after cadaveric renal transplantation. In three patients who achieved good renal function, the correction of volume overload, as reflected by reduction in weight and right atrial pressure, was associated with a steady fall in plasma ANP and a parallel decrease in both fractional excretion of sodium and plasma cyclic guanosine monophosphate. The fourth patient, with severe acute rejection, developed severe peripheral oedema, and fractional sodium excretion remained low despite high values of ANP.
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We measured plasma atrial natriuretic peptide (ANP) levels in 17 patients with newly diagnosed thyrotoxicosis. ANP was elevated compared to a group of healthy controls and fell to normal after treatment. Plasma cyclic guanosine monophosphate was also raised in untreated patients. Elevated circulating levels of ANP may play a part in the haemodynamic changes of hyperthyroidism.
A woman with a 21 year old history of systemic lupus erythematosus (SLE) is presented. During a period of low connective tissue disease activity she developed sudden difficulty in walking and after much investigation was found to have a primary lymphoma of the brain. She died 6 months after this diagnosis from meningeal spread, despite radiotherapy to the tumour. The association between SLE and lymphoma is discussed.
Thiocyanate or bromide increased the colour formed by nitrite reacting with sulfanilic acid and naphthylethylenediamine. If the colour reagents were added together with thiocyanate (final concentration, M/10), the colour intensity was doubled. If sulfanilic acid was added three minutes before addition of naphthylethylenediamine, the relationship between nitrite concentration and colour production was more linear in the presence of thiocyanate. This effect was due to thiocyanate catalysing the diazotization of sulfanilic acid and inhibiting the reaction of nitrite with naphthylethylenediamine. Bromide and thiocyanate are similar in their catalytic effects on nitrosation, and hydrobromic acid in glacial acetic acid is an effective reagent for denitrosation of nitrosamine. Although thiocyanate catalysed denitrosation of nitrosamines, the effect was small except with nitrosomethylaniline, which had also been found to be denitrosated by sulfanilic acid. Thiocyanate could not be used generally for the destruction of nitrosamines; it was also found to be ineffective as an alternative to hydrobromic acid in the estimation of nitrosamines.
Classical studies with murine embryonic kidneys (metanephroi) grown in organ culture or on the avian chorio-allantoic membrane have suggested that kidney endothelia arise by ingrowth or angiogenesis. More recent studies, however, indicate that glomerular capillaries and arterioles may form in situ by vasculogenesis when more realistic experimental conditions are deployed: these include glomerulogenesis after transplantation of metanephroi to the nephrogenic renal cortex of mice as well as development in oculo. This conclusion is supported by the finding that receptor tyrosine kinases such as VEGFR-1/2 and Tie-1, characteristic of endothelial precursors, are expressed in the metanephros at a stage when no patent vessels are apparent. Further studies are required to determine the origin of endothelial cells in renal vessels of larger calibre.
Development of epithelial organs requires co-ordinated interactions between epithelial and mesenchymal tissues. Studies using null mutant mice have indicated that the ret receptor and its ligand, glial cell line-derived neurotrophic factor (GDNF), are crucial for initiation of development of the metanephric kidney. However, the role of this signalling system in other branching organs has not been analysed. Here we describe expression studies of ret, GDNF, and a co-receptor for GDNF (GDNFR alpha) in the developing mouse metanephros, lung, and submandibular salivary gland. Also, we examined the role of this signalling system in the development of these organs in vitro. In situ hybridisation revealed differences in the spatial distribution of the three transcripts in the different organs. At the initiation of metanephric development, late on embryonic day 10 (E10), ret and GDNFR alpha were detected in the Wolffian duct (including the presumptive ureteric bud) whilst the presumptive metanephric, mesenchyme expressed GDNFR alpha and GDNF. Later in development, all three transcripts were restricted to the nephrogenic zone. In contrast, expression in the lung was not detectable by in situ hybridisation until after initiation of development, at E13.5. At this time ret was expressed throughout the epithelium; GDNF was detected throughout the mesenchyme, and GDNFR alpha was present in the proximal epithelium and mesenchyme only. Ret and GDNF were not detected in the epithelium or mesenchyme of the developing salivary gland, however, GDNFR alpha was expressed in the mesenchyme at E13.5 and E16.5. Functional studies demonstrated that in organ culture, GDNF significantly increased branching morphogenesis of the E11.5 metanephros, and induced the formation of ectopic ureteric buds from the base of the bud and from the Wolffian duct. The development of lung and salivary primordia were not affected under similar growth conditions. In a novel ureteric bud primary culture system, GDNF significantly increased cell numbers at 24 and 48 h. In cells cultured on laminin this increase was due to increased survival and proliferation, whereas in cells cultured on fibronectin, only survival was enhanced. Our data suggest that GDNF stimulates outgrowth of the ureteric bud, in part, by enhancing cell survival and possibly by increasing proliferation.
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Our previous observation that embryonic kidney tissue can develop and differentiate when transplanted into the parenchyma of mouse kidneys in the postnatal period provided an avenue for transferring novel genes into the mammalian kidney in vivo. Mouse metanephric tissue was infected ex vivo with a replication defective retrovirus which transduces the gene for beta-galactosidase. Seven to 21 days after transplantation of this tissue into neonatal and adult mouse kidneys, the expression of the gene, controlled by the viral long-terminal repeat promoter, was noted in approximately one-third of implants. Gene expression occurred predominantly in glomerular epithelial cells, but also in interstitial cells and in vascular structures. Polymerase chain reaction amplification of renal genomic DNA indicated the presence of viral DNA in 9 of 10 kidneys which had received metanephric implants into the neonatal renal cortex. These studies demonstrate the feasibility of short-term gene transfer into and expression within the mammalian kidney.
Gene transfer using retroviral vectors requires cell replication for insertion of the DNA provirus. Since the mitotic index of the mammalian kidney is very low, renal tubular cell replication was induced in adult rats as part of a regenerative response to the nephrotoxic injury induced by an intraperitoneal injection of folic acid. At 48 h, at the time of maximum 3H-thymidine incorporation, the left kidney was directly injected with a suspension of the Psi2 BAG retrovirus which transduces the beta-galactosidase gene. At 1-7 weeks after virus administration the left kidney was harvested. Using the polymerase chain reaction to amplify viral DNA, successful gene transfer was achieved in 8 of 15 kidneys. In 6 of 10 kidneys assessed histochemically positive staining for beta-galactosidase activity was detected in the cytoplasm of tubular epithelial cells. There was no evidence of gene expression in glomerular, vascular or endothelial cells. All analyses were negative in vehicle-injected kidneys and in the kidneys of animals which did not receive pretreatment with folic acid. These studies demonstrate the feasibility of gene transfer into the adult kidney provided that replication of specific cell types can be achieved.
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