A case of membranous nephropathy secondary to asymptomatic Graves' disease.

Although cases of secondary membranous nephropathy associated with autoimmune thyroid disease (AITD) have been reported, most of them, if not all, present with symptomatic thyroid disease. Here we report an asymptomatic case of AITD complicated with secondary membranous nephropathy. A 16-year-old girl was referred to our institute because of proteinuria found by an annual medical checkup. Urinalysis showed a urinary protein creatinine ratio (UPCR) of 3.0 g/gCre. Blood examination revealed that she had Graves' disease, although she did not have any symptoms of hyperthyroidism such as weight loss, anxiety, tremor, tachycardia, or eye symptoms. In a kidney biopsy, periodic acid silver-methenamine staining showed spike formation in the basement membrane. Electron microscopy showed electron-dense deposits on the epithelial side of the glomerular basement membrane. Immunofluorescent staining showed co-localization of thyroid peroxidase and IgG deposition along the glomerular capillary walls. A diagnosis of membranous nephropathy secondary to asymptomatic Graves' disease was made on the basis of results of the examinations. Treatment with thiamazole added to enalapril improved proteinuria (reduction of UPCR to 0.83 g/gCr) and hypoalbuminemia. Consideration should be given to the possibility of AITD in differential diagnosis of etiologies of membranous nephropathy even when typical symptoms of AITD are lacking.

The impact of elevation of serum uric acid level on the natural history of glomerular filtration rate (GFR) and its sex difference.

BACKGROUND: The impact of elevation of the serum uric acid level (SUA) on the natural history of glomerular filtration rate (GFR) remains controversial. METHODS: If elevation of SUA is a result, rather than a cause, of a decline in GFR, the relationship between SUA and GFR should be the same in the same population over years except for shifts by age-dependent reduction of GFR. We tested this hypothesis using data from two cohorts and a group of allopurinol-treated patients. RESULTS: In Cohort 1 consisting of urban residents aged 40.6 ± 9.0 years (n = 3 446), SUA was inversely correlated with estimated GFR (eGFR) in both men and women, and the slope of the SUA-eGFR relationship was steeper in women than in men. The slopes of the regression lines became significantly steeper after a 6-year interval in both sexes, and the change in the slope was larger in women. A similar sex difference in the SUA-eGFR relationship and 6-year change in the slope were observed in Cohort 2 consisting of rural town residents aged 61.7 ± 12.2 years (n = 404). Multiple regression analyses showed that explanatory factors of eGFR after a 6-year interval were age and SUA at baseline in both cohorts, and partial regression coefficients of SUA were more negative in women than in men. The SUA-eGFR relationship in allopurinol-treated patients (n = 346, 63.5 ± 13.3 years old) was similar to that in Cohort 2. CONCLUSIONS: The results indicate that elevation of SUA accelerates the yearly decline in eGFR and that women are more susceptible to urate-induced decline in eGFR.

Proteomic analysis reveals novel binding partners of dysbindin, a schizophrenia-related protein.

Schizophrenia is a complex mental disorder with fairly high level of heritability. Dystrobrevin binding protein 1, a gene encoding dysbindin protein, is a susceptibility gene for schizophrenia that was identified by family-based association analysis. Recent studies revealed that dysbindin is involved in the exocytosis and/or formation of synaptic vesicles. However, the molecular function of dysbindin in synaptic transmission is largely unknown. To investigate the signaling pathway in which dysbindin is involved, we isolated dysbindin-interacting molecules from rat brain lysate by combining ammonium sulfate precipitation and dysbindin-affinity column chromatography, and identified dysbindin-interacting proteins by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and liquid chromatography-tandem mass spectrometry. Proteins involved in protein localization process, including Munc18-1, were identified as dysbindin-interacting proteins. Munc18-1 was co-immunoprecipitated with dysbindin from rat brain lysate, and directly interacted with dysbindin in vitro. In primary cultured rat hippocampal neurons, a part of dysbindin was co-localized with Munc18-1 at pre-synaptic terminals. Our result suggests a role for dysbindin in synaptic vesicle exocytosis via interaction with Munc18-1.

Direct interaction of Dysbindin with the AP-3 complex via its mu subunit.

Genetic factors are important in the etiology of schizophrenia. Recent studies have revealed the association between genetic variation of Dysbindin (DTNBP1) and schizophrenia. Dysbindin is one of the essential components of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). BLOC-1 physically interacts with the adaptor protein (AP)-3 complex, which is essential for vesicle or protein sorting. However, it remains largely unknown how BLOC-1 interacts with the AP-3 complex. To investigate the binding mode of BLOC-1 and the AP-3 complex, we examined the relation between Dysbindin and the AP-3 complex and found that Dysbindin formed a complex with the AP-3 complex through the direct binding to its mu subunit. Dysbindin partially co-localized with the AP-3 complex in CA1 and CA3 of mouse hippocampus, and at presynaptic terminals and axonal growth cones of cultured hippocampal neurons. Suppression of Dysbindin results in the reduction of presynaptic protein expression and glutamate release. Thus, Dysbindin appears to participate in the exocytosis or sorting of the synaptic vesicle via direct interaction with the AP-3 complex.

DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1.

Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3epsilon. 14-3-3epsilon is involved in the proper localization of NUDEL and LIS1 in axons. Although the functional significance of this complex in neuronal development has been reported, the transport mechanism of the complex into axons and their functions in axon formation remain essentially unknown. Here we report that Kinesin-1, a motor protein of anterograde axonal transport, was identified as a novel DISC1-interacting molecule. DISC1 directly interacted with kinesin heavy chain of Kinesin-1. Kinesin-1 interacted with the NUDEL/LIS1/14-3-3epsilon complex through DISC1, and these molecules localized mainly at cell bodies and partially in the distal part of the axons. DISC1 partially colocalized with Kinesin family member 5A, NUDEL, LIS1, and 14-3-3epsilon in the growth cones. The knockdown of DISC1 by RNA interference or the dominant-negative form of DISC1 inhibited the accumulation of NUDEL, LIS1, and 14-3-3epsilon at the axons and axon elongation. The knockdown or the dominant-negative form of Kinesin-1 inhibited the accumulation of DISC1 at the axons and axon elongation. Furthermore, the knockdown of NUDEL or LIS1 inhibited axon elongation. Together, these results indicate that DISC1 regulates the localization of NUDEL/LIS1/14-3-3epsilon complex into the axons as a cargo receptor for axon elongation.

DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2.

Disrupted-in-Schizophrenia-1 (DISC1) is a candidate gene for susceptibility of schizophrenia. In the accompanying paper (Taya et al., 2006), we report that DISC1 acts as a linker between Kinesin-1 and DISC1-interacting molecules, such as NudE-like, lissencephaly-1, and 14-3-3epsilon. Here we identified growth factor receptor bound protein 2 (Grb2) as a novel DISC1-interacting molecule. Grb2 acts as an adaptor molecule that links receptor tyrosine kinases and the Ras-extracellular signal-regulated kinase (ERK) pathway. DISC1 formed a ternary complex with Grb2 and kinesin heavy chain KIF5A of Kinesin-1. In cultured rat hippocampal neurons, both DISC1 and Grb2 partially colocalized at the distal part of axons. Knockdown of DISC1 or kinesin light chains of Kinesin-1 by RNA interference inhibited the accumulation of Grb2 from the distal part of axons. Knockdown of DISC1 also inhibited the neurotrophin-3 (NT-3)-induced phosphorylation of ERK-1/2 at the distal part of axons and inhibited NT-3-induced axon elongation. These results suggest that DISC1 is required for NT-3-induced axon elongation and ERK activation at the distal part of axons by recruiting Grb2 to axonal tips.

Relationship between renal artery stenosis and intrarenal damage in autopsy subjects with stroke.

BACKGROUND: In patients with cardiovascular disease (CVD), renal dysfunction is a risk factor for the prognosis, but substantial evidence is still lacking about the relationship between clinical characteristics and renal histology. The aim of our study was to evaluate the relationship between the extent of renal parenchymal damage, renal artery stenosis (RAS) and clinical characteristics in autopsy subjects with stroke. METHODS: During the 17-year period 1980-1997, 2167 subjects were autopsied at the National Cardiovascular Center. We studied retrospectively all the autopsy cases aged 40 years and older who had a history of stroke. Thus, 346 subjects remained and they were classified into two groups. Thirty-six subjects had RAS (group A). Three hundred and ten subjects had no RAS, and we randomly chose 102 subjects among them (group B). We evaluated renal parenchymal damage using a semi-quantitative chronic damage score. RESULTS: The average overall chronic damage score was significantly higher in the stenosed kidneys of group A than in the non-stenosed kidneys of group B (9.0+/-2.6 vs 7.0+/-2.7). The contralateral kidneys of group A had a tendency to have milder renal damage than stenosed kidneys. Furthermore, the total score was higher in the subjects with hypertension, diabetes mellitus, proteinuria, renal insufficiency and CVD than in the subjects without such complications. The total score had a significant association with RAS, proteinuria, renal insufficiency, CVD and weight of the kidney. CONCLUSIONS: In autopsy subjects with stroke, we demonstrated that co-existing renal parenchymal damage was more severe in the subjects with RAS, hypertension, diabetes mellitus, proteinuria and renal insufficiency than those without such complications. The presence of RAS, impaired renal function and proteinuria was closely correlated with the severity of renal parenchymal damage.

Influence of plasma aldosterone on left ventricular geometry and diastolic function in treated essential hypertension.

Since aldosterone is known to promote interstitial fibrosis in cardiac tissues, it is possible that aldosterone may influence cardiac structure and function. In the present study, we investigated whether plasma aldosterone concentration (PAC) is related to the distinct patterns of left ventricular (LV) geometry and LV diastolic function in treated essential hypertension. In 92 patients with chronically treated essential hypertension, two-dimensional and Doppler echocardiographic examinations were performed and LV inflow velocities were measured for evaluation of LV diastolic function. When patients were divided into four groups by the different LV geometric patterns, PAC in patients with eccentric hypertrophy was significantly higher than in those with concentric hypertrophy (15.2+/-2.1 vs. 10.0+/-0.7 ng/dl, p<0.01). However, the ratio of the peak velocity of early diastolic filling to that of atrial filling (EIA), an index of LV diastolic function, was significantly decreased in patients with concentric hypertrophy compared with those showing normal geometry. In the relationship between PAC and LV diastolic function, PAC was negatively correlated with EIA (r=-0.35, p<0.05) only in the subgroup with normal relative wall thickness (i.e., without the concentric change in LV geometry). A multiple linear regression analysis showed that PAC was one of the independent determinants of E/A in the overall subject group. These observations indicate that PAC is associated with the eccentric change in LV geometry in patients with treated essential hypertension and also suggest that the increase in PAC participates in the impairment of LV diastolic function apart from the concentric change in LV geometry, although concentric hypertrophy clearly impairs LV diastolic function.