Products of red blood cell degradation inhibit responsiveness of the erythropoietin oxygen sensor.
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.
Necas
E
E
Department of Pathophysiology, First Medical Faculty, Charles University, Prague, Czech Republic.
D000818:Animals; D015152:Blotting, Northern; D004912:Erythrocytes / Q000378:metabolism*; D004921:Erythropoietin / Q000378:metabolism / Q000502:physiology*; D006461:Hemolysis / Q000502:physiology; D006358:Hot Temperature; D000860:Hypoxia / Q000097:blood / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D010100:Oxygen / Q000097:blood*; D012333:RNA, Messenger / Q000096:biosynthesis
D012333:RNA, Messenger; D004921:Erythropoietin; D010100:Oxygen