Tissue hypoxia is less effective in increasing erythropoietin plasma levels in animals with post-transfusion polycythaemia. Since more red blood cells are decomposed under this condition, the effects of exogenous haemin and of lysed or heat-damaged red blood cells on activation of the erythropoietin gene have been studied in mice rendered hypoxic. Total RNA was extracted from the kidney and the liver and subjected to northern blot analysis with a probe containing part of the murine erythropoietin gene. Blood plasma was collected and erythropoietin levels were determined by radioimmunoassay. Erythropoietin gene activation was suppressed by haemin and increased red blood cell haemolysis. Tin (Sn) protoporphyrin, a haeme analogue which cannot bind oxygen, did not share the effect of haemin. On the other hand, when injected with haemin, Sn-protoporphyrin potentiated the suppressive effect of haemin, probably through inhibition of haemin catabolism. We conclude that the intracellular haeme concentration inhibits the kidney oxygen sensor and that this inhibition, mediated by products red blood cell degradation, is a physiological safeguard mechanism against excessive polycythaemia and its deleterious effects upon blood circulation.
Tagging cells of experimental organisms with genetic markers is commonly used in biomedical research. Insertion of artificial gene constructs can be highly beneficial for research as long as this tagging is functionally neutral and does not alter the tissue function. The transgenic UBC-GFP mouse has been recently found to be questionable in this respect, due to a latent stem cell defect compromising its lymphopoiesis and significantly influencing the results of competitive transplantation assays. In this study, we show that the stem cell defect present in UBC-GFP mice negatively affects T-lymphopoiesis significantly more than B-lymphopoiesis. The production of granulocytes is not negatively affected. The defect in T-lymphopoiesis causes a low total number of white blood cells in the peripheral blood of UBC-GFP mice which, together with the lower lymphoid/myeloid ratio in nucleated blood cells, is the only abnormal phenotype in untreated UBCGFP mice to have been found to date. The defective lymphopoiesis in UBC-GFP mice can be repaired by transplantation of congenic wild-type bone marrow cells, which then compensate for the insufficient production of T cells. Interestingly, the wild-type branch of haematopoiesis in chimaeric UBC-GFP/wild-type mice was more active in lymphopoiesis, and particularly towards production of T cells, compared to the lymphopoiesis in normal wild-type donors.