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During embryonic development, some hypoxia occurs due to incipient vascularization. Under hypoxic conditions, gene expression is mainly controlled by hypoxia-inducible factor 1 (HIF-1). The activity of this transcription factor can be altered by the exposure to a variety of compounds; among them is cadmium (Cd), a nephrotoxic heavy metal capable of crossing the placenta and reaching fetal kidneys. The goal of the study was to determine Cd effects on HIF-1 on embryonic kidneys. Pregnant Wistar rats were exposed to a mist of isotonic saline solution or CdCl₂ (D Del = 1.48 mg Cd/kg/day), from gestational day (GD) 8 to 20. Embryonic kidneys were obtained on GD 21 for RNA and protein extraction. Results show that Cd exposure had no effect on HIF-1α and prolyl hydroxylase 2 protein levels, but it reduced HIF-1 DNA-binding ability, which was confirmed by a decrease in vascular endothelial growth factor ( VEGF ) mRNA levels. In contrast, the protein levels of VEGF were not changed, which suggests the activation of additional regulatory mechanisms of VEGF protein expression to ensure proper kidney development. In conclusion, Cd exposure decreases HIF-1-binding activity, posing a risk on renal fetal development.

Endogenous Ca(2+)-activated Cl(-) channels (CaCC) demonstrate biophysical and pharmacological properties that are well represented in cells overexpressing anoctamin 1 (Ano 1, TMEM16A), a protein that has been identified recently as CaCC. Proteins of the anoctamin family (anoctamin 1-10, TMEM16A-K) are widely expressed. The number of reports demonstrating their physiological and clinical relevance is quickly rising. Anoctamins gain additional interest through their potential role in cell volume regulation and malignancy. Available data suggest that Ano 1 forms stable dimers and probably liaise with accessory proteins such as calmodulin or other anoctamins. In order to understand how anoctamins produce Ca(2+)-activated Cl(-) currents, it will be necessary to obtain better insight into their molecular structure, interactions with partner proteins, and mode of activation.

It was recently proposed that, in rat pancreatic islets, the production of bicarbonate accounts for the major fraction of the carbon dioxide generated by the oxidative catabolism of nutrient insulin secretagogues. In search of the mechanism(s) supporting the membrane transport of bicarbonate, the possible role of the electrogenic Na(+)-HCO(3) (-)-cotransporters NBCe1-A and NBCe1-B in rat pancreatic islet cells was investigated. Expression of NBCe1-A and NBCe1-B in rat pancreatic islet cells was documented by RT-PCR, western blotting, and immunocytochemistry. The latter procedure suggested a preferential localization of NBCe1-B in insulin-producing cells. Tenidap (3-100 microM), previously proposed as an inhibitor of NBCe1-A-mediated cotransport in proximal tubule kidney cells, caused a concentration-related inhibition of glucose-stimulated insulin secretion. It also inhibited 2-ketoisocaproate-induced insulin release and to a relatively lesser extent, the secretory response to L: -leucine. Tenidap (50-100 microM) also inhibited the metabolism of D: -glucose in isolated islets, increased (22)Na net uptake by dispersed islet cells, lowered intracellular pH and provoked hyperpolarization of plasma membrane in insulin-producing cells. This study thus reveals the expression of the electrogenic Na(+)-HCO(3) (-)-cotransporters NBCe1-A and NBCe1-B in rat pancreatic islet cells, and is consistent with the participation of such transporters in the process of nutrient-stimulated insulin secretion.

Anemia of endstage renal failure improves shortly after kidney transplantation. However, in about 10% of transplanted patients polycythemia occurs. By use of a sensitive in vitro bioassay the pathogenetic role of erythropoietin (Ep) was investigated in 12 patients with post-transplant erythrocytosis (PTE), and compared to 12 non-PTE patients. The mean Ep of 160 mU/ml was significantly elevated in patients with PTE as compared to 25 mU/ml of 36 healthy controls, whereas, the mean Ep of 24 mU/ml in non-PTE patients did not differ significantly from healthy controls. To further elucidate the mechanism of inappropriate Ep production, selective venous catheterization of native and transplanted kidneys was performed in six patients. In four PTE patients the mean Ep in native kidney veins of 110 mU/ml was significantly higher than the peripheral Ep of 66 mU/ml, whereas, mean Ep in kidney graft veins was 51 mU/ml. In contrast, in two non-PTE patients no significant difference between mean Ep from native and transplanted kidney veins was observed. We conclude that some patients escape from normal feedback regulation either due to autonomous Ep production or due to feedback regulation at an elevated level of hematocrit and that inappropriate Ep production originates from the diseased native kidneys.