Sex effects of dietary protein source and acid load on renal and bone status in the Pahenu2 mouse model of phenylketonuria.

Bridget M Stroup,Emma M Lankey,Sangita G Murali,Denise M Ney,Denise J Schwahn,Emily A Sawin,Hans Peter Bächinger

doi:10.14814/phy2.14251

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.

Highlights

Phenylalanine hydroxylase (PAH; EC 1.14.16.1) deficiency commonly called phenylketonuria (PKU) is an autosomal recessive inborn error of Phe metabolism resulting in an inability to synthesize Tyr and elevated concentrations of its precursor Phe in blood and brain (Singh et al 2014; Vockey et al 2014)
Evidence in humans with PKU and the Pahenu2 murine model of Pah deficiency shows an association between long-term adherence to a low-Phe diet supplemented with amino acid (AA) and the presence of chronic kidney disease (Hennermann et al 2013; Stroup et al 2017; Burton et al 2018), as well as skeletal fragility characterized by low bone mineral density (BMD) and increased risk of fractures (Modan-Moses et al 2007; Groot et al 2012; Hansen and Ney, 2014; Coakley et al 2016; Choukair et al 2017)
Our research indicates that the standard low-Phe, highacid AA diet used in studies with the Pahenu2 murine model of Pah deficiency induces metabolic stress and increases renal workload based on greater renal mass, fluid intake, and polyuria in both PahÀ/À and wild-type (WT) mice (Solverson et al 2012)

Summary

Introduction

Phenylalanine hydroxylase (PAH; EC 1.14.16.1) deficiency commonly called phenylketonuria (PKU) is an autosomal recessive inborn error of Phe metabolism resulting in an inability to synthesize Tyr and elevated concentrations of its precursor Phe in blood and brain (Singh et al 2014; Vockey et al 2014). Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society Evidence in humans with PKU and the Pahenu murine model of Pah deficiency shows an association between long-term adherence to a low-Phe diet supplemented with AAs and the presence of chronic kidney disease (Hennermann et al 2013; Stroup et al 2017; Burton et al 2018), as well as skeletal fragility characterized by low bone mineral density (BMD) and increased risk of fractures (Modan-Moses et al 2007; Groot et al 2012; Hansen and Ney, 2014; Coakley et al 2016; Choukair et al 2017)

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