Sex effects of dietary protein source and acid load on renal and bone status in thePah^enu2mouse model of phenylketonuria

Abstract

The low‐phenylalanine (Phe) diet with amino acid (AA) medical foods is associated with low bone mineral density (BMD) and renal dysfunction in human phenylketonuria (PKU). Our objective was to determine if diets differing in dietary protein source and acid load alter bone and renal outcomes in Pah−/− and wild‐type (WT) mice. Female and male Pah−/− (Pahenu2/enu2) and WT littermates (C57BL/6 background) were fed high‐acid AA, buffered AA (BAA), glycomacropeptide (GMP), or high‐Phe casein diets from 3 to 24 weeks of age. The BAA diet significantly reduced the excretion of renal net acid and ammonium compared with the AA diet. Interestingly, the BAA diet did not improve renal dilation in hematoxylin and eosin (H&E) stained renal sections, femoral biomechanical parameters, or femoral bone mineral content (BMC). Significantly lower femoral BMC and strength occurred in Pah−/− versus WT mice, with greater decline in female Pah−/− mice. Polyuria and mild vacuolation in the proximal convoluted tubules were observed in male Pah−/− and WT mice fed the high‐acid AA diet versus absent/minimal cortical vacuolation in males fed the GMP, BAA, or casein diets. Vacuole contents in male mice were proteinaceous. Cortical vacuolation was absent in female mice. Dilated medullary tubules were observed in all Pah−/− mice, except for male Pah−/− mice fed the GMP diet. In summary, the PKU genotype and diet showed differential effects on renal and bone status in male and female mice. Renal status improved in male Pah−/− mice fed the GMP diet.

Nutrition, Microbiota and Role of Gut-Brain Axis in Subjects with Phenylketonuria (PKU): A Review

“…In this field, the research on the features of the GMP polypeptide has spanned in different directions to find that GMP can bind and inactivate toxins of E. coli and Vibrio cholerae [221], inhibit the adhesion of cariogenic bacteria [222], enhance zinc absorption [223], increase cytokine production [224] and decrease stimulation of T-helper1 lymphocytes in rats [225], and act as an anti-inflammatory in different models [226,227]. Among others, GMP has been studied for the control of satiety, although with conflicting results [228][229][230], for the effects on bone size and strength [231][232][233], and interestingly for its role as prebiotic. The latter is thought to be based on the fact that GMP shows a high degree of glycosylation that includes mucin-like oligosaccharide chains that contain sialic acid, galactose, and galactosamine.…”

“…inflammatory in different models [226,227]. Among others, GMP has been studied for the control of satiety, although with conflicting results [228][229][230], for the effects on bone size and strength [231][232][233], and interestingly for its role as prebiotic. The latter is thought to be based on the fact that GMP shows a high degree of glycosylation that includes mucin-like oligosaccharide chains that contain sialic acid, galactose, and galactosamine.…”

Long-Term Renal Function in Adult Patients with Phenylketonuria

“…Hennermann and her colleagues detected impaired renal function, proteinuria, and arterial hypertension in ETPKU patients on a lifelong diet [27]. In a study performed with PKU mice models (Pah enu2 ), it was found that chronic ingestion of AAs had a negative effect on renal function, compared with natural protein intake from food [29].…”