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1.
Nephrol Dial Transplant ; 35(10): 1678-1688, 2020 10 01.
Article in English | MEDLINE | ID: mdl-32596728

ABSTRACT

BACKGROUND: Chronic hypoxia may play a pivotal role in the development of diabetic nephropathy (DN). However, the precise mechanisms underlying progressive hypoxia-induced glomerular injury remain unclear. METHODS: We housed db/db mice in a hypoxia chamber (12% O2) for up to 16 weeks beginning at 8 weeks of age. Various urine, serum and kidney abnormalities and glomerular messenger RNA (mRNA) expression were compared with those in age-matched db/db mice housed under normoxia. RESULTS: Levels of urinary albumin and podocalyxin (PCX) were significantly higher in hypoxic mice early during hypoxia. Ultracentrifugation of urine samples revealed that podocytes in the hypoxic mice shed PCX-positive microparticles into the urine. After 16 weeks of hypoxia, the mice also had higher hematocrits with lower serum glucose and various degrees of mesangiolytic glomerulosclerosis with microaneurysms and the infrequent occurrence of nodular lesions. Immunohistologically, hypoxic mice showed significantly decreased endothelial cell densities early during hypoxia and decreased podocyte densities later. In both hypoxic and normoxic mice, glomerular macrophage and transforming growth factor-ß1 (TGF-ß1) staining significantly increased with aging, without changes in vascular endothelial growth factor or endothelial nitric oxide synthase (eNOS). Glomerular mRNA expression of monocyte chemoattractant protein-1, eNOS and TGF-ß1 was significantly enhanced in the hypoxic mice. CONCLUSIONS: These results indicate that chronic hypoxia induces advanced glomerulosclerosis with accelerated albuminuria triggered by mesangiolysis and podocyte injury in a murine model of DN.


Subject(s)
Diabetes Complications/etiology , Diabetes Mellitus, Experimental/complications , Diabetic Nephropathies/etiology , Glomerular Mesangium/pathology , Hypoxia/physiopathology , Podocytes/pathology , Animals , Diabetes Complications/metabolism , Diabetes Complications/pathology , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Glomerular Mesangium/metabolism , Male , Mice , Mice, Inbred Strains , Nitric Oxide Synthase Type III/metabolism , Podocytes/metabolism , Transforming Growth Factor beta1/metabolism , Vascular Endothelial Growth Factor A/metabolism
2.
Clin Nephrol ; 83(5): 301-8, 2015 May.
Article in English | MEDLINE | ID: mdl-25295576

ABSTRACT

We report the case of a 42-yearold woman diagnosed with heterozygous Fabry disease (FD) due to a novel α-galactosidase A Pro210Ser mutation and exhibiting a unique distribution of synaptopodin within podocytes. The patient was referred to our hospital with moderate proteinuria, and a renal biopsy was performed. Light microscopic examination of the specimen revealed diffuse global enlargement of podocytes, which also showed foamy changes. Electron microscopy revealed abundant myeloid bodies in podocytes and focal mitochondrial abnormalities within the tubules. The patient exhibited none of the characteristic symptoms of FD except hypohidrosis and had no obvious family history. Genetic analysis revealed a novel missense mutation (Pro210Ser) in the α-galactosidase A gene. She was ultimately diagnosed with FD based on immunohistochemical staining indicating large amounts of accumulated globotriaosylceramide in her podocytes, detection of urinary globotriaosylceramide secretion using high-performance thin-layer chromatography/ immunostaining, and structural modeling of the mutated α-galactosidase A (Pro210Ser). Immunostaining of the swollen and foamy podocytes using podocyte-associated antibodies (against podocalyxin, Wilms tumor-1, vimentin, and synaptopodin) revealed a unique distribution of synaptopodin surrounding globotriaosylceramide. To our knowledge, this is the first report of immunohistologically detected synaptopodin upregulation in foamy podocytes in a patient with FD.


Subject(s)
Fabry Disease/genetics , Heterozygote , Microfilament Proteins/analysis , Mutation, Missense , Podocytes/chemistry , Vacuoles/chemistry , alpha-Galactosidase/genetics , Adult , Biopsy , DNA Mutational Analysis , Enzyme Replacement Therapy , Fabry Disease/diagnosis , Fabry Disease/drug therapy , Fabry Disease/enzymology , Female , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Microscopy, Electron , Microscopy, Fluorescence , Models, Molecular , Phenotype , Podocytes/ultrastructure , Trihexosylceramides/analysis , Vacuoles/ultrastructure , alpha-Galactosidase/therapeutic use
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