Hepatocyte growth factor-stimulated renal tubular mitogenesis: effects on expression of c-myc, c-fos, c-met, VEGF and the VHL tumour-suppressor and related genes.

Hepatocyte growth factor (HGF/SF) is a potent renal proximal tubular cell (PTEC) mitogen involved in renal development. HGF/SF is the functional ligand for the c-met proto-oncogene, and germline c-met mutations are associated with familial papillary renal cell carcinoma. Somatic von Hippel-Lindau disease tumour-suppressor gene (VHL) mutations are frequently detected in sporadic clear cell renal cell carcinomas (RCC), and germline VHL mutations are the commonest cause of familial clear cell RCC. pVHL binds to the positive regulatory components of the trimeric elongin (SIII) complex (elongins B and C) and has been observed to deregulate expression of the vascular endothelial growth factor (VEGF) gene. HGF/SF has similarly been reported to up-regulate expression of the VEGF gene in non-renal experimental systems. To investigate the mechanism of HGF/SF action in PTECs and, specifically, to examine potential interactions between the HGF/c-met and the VHL-mediated pathways for renal tubular growth control, we have isolated untransformed PTECs from normal kidneys, developed conditions for their culture in vitro and used these cells to investigate changes in mRNA levels of the VHL, elongin A, B and C, VEGF, c-myc, c-fos and c-met genes after HGF/SF exposure. Significant elevations in the mRNA levels of VEGF, c-myc, c-fos, c-met and elongins A, B and C, but not VHL, were detected after HGF/SF stimulation of human PTECs (P < 0.02), with a consistent order of peak levels observed over successive replicates (c-fos at 1 h, VEGF at 2-4 h, c-myc, at 4 h, followed by c-met and all three elongin subunits at 8 h). This study highlights the spectrum of changes in gene expression observed in PTECs after HGF/SF stimulation and has identified possible candidate mediators of the HGF/SF-induced mitogenic response. Our evidence would suggest that the changes in PTEC VEGF expression induced by HGF/SF are mediated by a VHL-independent pathway.

Thyroid function in idiopathic oedema.

BACKGROUND: The role of abnormal thyroid function in the aetiology of idiopathic oedema is unclear. Previous studies of small samples of patients have suggested a high prevalence of latent hypothyroidism and a possible deiodination defect in the conversion of T4 to T3 in this condition. There is a need to clarify the possible significance of abnormal thyroid function in a larger sample of idiopathic oedema patients. OBJECTIVE: The study was undertaken to compare basal thyroid function in idiopathic oedema patients and in an age and sex-matched control group. PATIENTS AND DESIGN: After excluding one idiopathic oedema patient and three control subjects with abnormal thyroid function, basal thyroid function was compared in 44 idiopathic oedema patients and in 44 age and sex-matched controls. MEASUREMENTS: Basal thyroid function was assessed in patient and control groups by measuring serum T4, fT4, T3, fT3 and TSH by standard methods. RESULTS: There were no significant differences in basal thyroid function between patient and control groups except for an elevated mean fT4 concentration in the idiopathic oedema group (P = 0.03). Exclusion of patients and controls taking oestrogen abolished this difference. T4:T3 ratios were similar in patient and control groups. CONCLUSION: Abnormalities of basal thyroid function are uncommon in patients with idiopathic oedema and appear unrelated to the pathogenesis of this disorder. Similar T4:T3 ratios between patient and control groups exclude a deiodination defect in idiopathic oedema.

The role of diuretics in the aetiology of idiopathic oedema.

The hypothesis that diuretic use and abuse and other purging behaviours cause idiopathic oedema was investigated in 102 patients. Of 91 symptomatic idiopathic oedema patients tested at referral, 16 (17.6%) had diuretic and four (4.4%) laxative in their urine. None had grossly disturbed serum urea and electrolytes. Examination of primary care records from 41 idiopathic oedema patients who denied current diuretic consumption, and denied or were uncertain about past consumption, showed that 20 had not been prescribed diuretics by their general practitioners at any time; a further 18 had not been prescribed diuretics for between seven months and 12 years before referral. The absence of evidence of plasma volume depletion (as judged by similar concentrations of mean serum urea, creatinine, total protein and albumin in patient and age-matched control groups) suggests that neither systematic diuretic and laxative use or abuse, nor episodic overeating and vomiting were responsible for symptoms of idiopathic oedema in our patients. Idiopathic oedema has a strong genetic basis, and correction of major and minor risk factors for this condition leads to substantial amelioration of symptoms in most cases.

Artificial ultraviolet whole-body radiation does not modify serum lipoprotein, plasma fibrinogen, plasminogen or antithrombin III concentrations in post-myocardial infarction patients.

The relationship of ischaemic heart disease (IHD) to seasonal and latitude variation has prompted speculation that exposure to the ultraviolet component of solar radiation may reduce IHD risk. This hypothesis was partially tested by exposing 14 post-myocardial infarction patients to a 6 week course of artificial whole-body ultraviolet radiation (UVR). Serum lipoprotein and plasma coagulation factor concentrations were measured before and after the course of UVR. Results were compared with similar measurements from a placebo-controlled group of 13 post-myocardial patients. Despite a more than two-fold rise in mean serum 25-OHD, serum lipoprotein and plasma fibrinogen, antithrombin III and plasminogen concentrations did not change significantly in the UVR group. Significant but minor change in prothrombin time and thrombin time in the placebo group appear unlikely to be of biological significance. Seasonal and latitude variation in these IHD risk factors appear unrelated to corresponding variation in solar UVR exposure.