Proteinuria in AMPD2‐deficient mice

Abstract

The AMPD2 gene, a member of the AMPD gene family encoding AMP deaminase, is widely expressed in nonmuscle tissues including kidney, although its functions have not been fully elucidated. In this study, we studied the function of the AMPD2 gene by establishing AMPD2-deficient model animal. We established AMPD2 knockout mice by using gene transfer and homologous recombination in murine ES cells and studied phenotypes and functions in the kidneys of these animals. AMPD activity was decreased from 22.9 mIU ⁄ mg protein to 2.5 mIU ⁄ mg protein in the kidneys of AMPD knockout mice. In addition to changes in nucleotide metabolism in the kidneys, proteinuria was found in 3-week-old AMPD2 knockout mice, followed by a further increment up to a peak level at 6 weeks old (up to 0.6 g ⁄ dL). The major protein component in the urine of AMPD2 knockout mice was found to be albumin, indicating that AMPD2 may have a key role in glomerular filtration. Indeed, an ultrastructure study of glomerulus specimens from these mice showed effacement of the podocyte foot processes, resembling minimal-change nephropathy in humans. Based on our results, we concluded that AMPD2 deficiency induces imbalanced nucleotide metabolism and proteinuria, probably due to podocyte dysfunction.

AMPD2 Regulates GTP Synthesis and Is Mutated in a Potentially Treatable Neurodegenerative Brainstem Disorder

“…In order to determine if these alterations in nucleotide levels are apparent in intact brain, we studied Ampd2 and Ampd3 knockout (KO) mice (Cheng et al, 2012; Toyama et al, 2012). The absence of histological phenotype in Ampd2 KO brain (Figure 5A) and the co-expression of Ampd2 and Ampd3 in embryonic and postnatal mouse brains, both contributing equally to brain AMP deaminase activity (Figure 5B–C), prompted us to test for functional redundancy by generating Ampd2 and Ampd3 double knockout mice (DKO), which were born in the expected Mendelian ratio.…”

“…Ampd2 (−/−) mice were previously generated (Toyama et al, 2012) and Ampd3 (−/−) were either generated by us using ES cell clone EPD0043_3_B02 generated by the Wellcome Trust Sanger Institute (www.komp.org) or from previous publication (Cheng et al, 2012). …”

Role of AMPD2 in impaired glucose tolerance induced by high fructose diet

“…On the other hand, an alternative mechanism in the kidneys could explain these metabolic changes. AMPD2 is known to be expressed in the kidneys, which lose AMPD2 protein immunoreactivity in the presence of Ampd2 deficiency [11]. In addition, GLUT5, a specific transporter of fructose, has been detected in kidney as well as liver tissues [5].…”

“…Generation of C57BL/6 WT (control) and Ampd2- deficient homozygous ( Ampd2  −/−: A2 −/−) mice was performed as previously described [11]. Animals were housed in an SPF environment with a 12-h light-dark cycle and constant temperature (25 °C).…”

“…AMPD2 is one of three different AMPD isoforms and exclusively distributed from the liver, though has also been detected in other organs such as the kidneys and brain [11]. In humans, a mutation of the Ampd2 gene is related to pontocerebellar hypoplasia [12], while it is associated with nephrotic syndrome in mice [13].…”