Serum erythropoietin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function

By use of the fetal mouse liver cell assay, serum erythropoietin (SEp) concentration was measured in 135 patients at various stages of chronic renal failure and in 59 healthy subjects. In patients with creatinine clearances (CCr) ranging from 2 to 40 ml/min/1.73 sq m, endocrine renal function was found to deteriorate in parallel to excretory renal function. The known negative correlation between SEp and hematocrit (Hct) was not apparent, probably because of the loss of renal mass accompanying progress of anemia and renal insufficiency. In contrast, in patients with minimal variation of residual excretory renal function, as in individual patients investigated repeatedly within a short period of time, changes of Hct were always accompanied by opposite changes of corresponding SEp concentrations. Thus, patients with chronic renal failure have a sustained regulatory feedback mechanism between Hct and SEp, which probably works at a lower level.</jats:p

Serum erythropoietin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function

Abstract By use of the fetal mouse liver cell assay, serum erythropoietin (SEp) concentration was measured in 135 patients at various stages of chronic renal failure and in 59 healthy subjects. In patients with creatinine clearances (CCr) ranging from 2 to 40 ml/min/1.73 sq m, endocrine renal function was found to deteriorate in parallel to excretory renal function. The known negative correlation between SEp and hematocrit (Hct) was not apparent, probably because of the loss of renal mass accompanying progress of anemia and renal insufficiency. In contrast, in patients with minimal variation of residual excretory renal function, as in individual patients investigated repeatedly within a short period of time, changes of Hct were always accompanied by opposite changes of corresponding SEp concentrations. Thus, patients with chronic renal failure have a sustained regulatory feedback mechanism between Hct and SEp, which probably works at a lower level.</jats:p

GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Aβ42

Processing of the amyloid precursor protein (APP) by β- and γ-secretases leads to the generation of amyloid-β (Aβ) peptides with varying lengths. Particularly Aβ42 contributes to cytotoxicity and amyloid accumulation in Alzheimer's disease (AD). However, the precise molecular mechanism of Aβ42 generation has remained unclear. Here, we show that an amino-acid motif GxxxG within the APP transmembrane sequence (TMS) has regulatory impact on the Aβ species produced. In a neuronal cell system, mutations of glycine residues G29 and G33 of the GxxxG motif gradually attenuate the TMS dimerization strength, specifically reduce the formation of Aβ42, leave the level of Aβ40 unaffected, but increase Aβ38 and shorter Aβ species. We show that glycine residues G29 and G33 are part of a dimerization site within the TMS, but do not impair oligomerization of the APP ectodomain. We conclude that γ-secretase cleavages of APP are intimately linked to the dimerization strength of the substrate TMS. The results demonstrate that dimerization of APP TMS is a risk factor for AD due to facilitating Aβ42 production