Diabetes mellitus complicates pregnancies, leading to diseases in adult life in the offspring. Asymmetric dimethylarginine (ADMA) is increased in diabetes mellitus, kidney disease, and hypertension. We tested whether maternal diabetes causes increased ADMA in rats, resulting in kidney disease and hypertension in the adult offspring, and whether these can be prevented by maternal citrulline supplementation. Newborn female and pregnant Sprague-Dawley rats were injected with streptozotocin (STZ), which made up the nSTZ and STZ models, respectively. For the STZ model, 4 groups of male offspring were killed at age 3 months: the control, STZ, and Cit and STZ+Cit (control and STZ rats treated with 0.25% l-citrulline solution, respectively) groups. The nSTZ rats had lower nephron numbers. The renal level of ADMA was higher in the nSTZ rats than in controls. The STZ group developed kidney injury, renal hypertrophy, and elevated blood pressure at the age of 12 weeks. These conditions were found to be associated with increased ADMA levels, decreased nitric oxide (NO) production, and decreased dimethylarginine dimethylaminohydrolase (DDAH) activity in the kidney. In addition, ADMA caused a nephron deficit in cultured rat metanephroi. Maternal citrulline supplementation prevented hypertension and kidney injury, increased the renal DDAH-2 protein level, and restored the levels of ADMA and NO in the STZ+Cit group. Reduced nephron number and increased ADMA contribute to adult kidney disease and hypertension in offspring of mothers with STZ-induced diabetes. Manipulation of the ADMA-NO pathway by citrulline supplementation may be a potential approach to prevent these conditions.
Inflammatory processes can stimulate renal epithelial cells to release cytokines, chemoattractants and matrix proteins into the interstitium, thus contributing to interstitial injury during acute allograft rejection. To test the role of interleukin 17 (IL-17) in this process, cultured human renal epithelial cells (hRECs) were first established and treated with or without human IL-17 (hIL-17) for 2, 4, 8 and 10 h in vitro. Significant elevations of IL-6 and IL-8 levels were noted in the supernatants in a dose-dependent and time-dependent manner, as also for IL-6 mRNA expression. Secondly, using a rat acute allograft rejection model, the correlation between IL-17 expression and histopathological changes was serially studied. The results demonstrated that increased expression of IL-17 protein on infiltrating mononuclear cells (MNCs) was detectable on day 2. This corresponds to the borderline change of acute rejection according to the Banff classification, and it increased progressively to day 5. Serial study of IL-6, IL-8 and IL-17 mRNA expression of the renal allograft confirmed IL-17 mRNA expression in the allograft early on post-transplant day 2, whereas IL-6 and IL-8 expression started on day 3. Thirdly, IL-17 expression was observed in human renal allograft and urinary sediment. IL-17 protein expression was found in human subclinical (borderline) rejection renal allograft biopsy tissue and none in biopsy tissue not showing any evidence of rejection. There was also a 100% detectable rate of IL-17 mRNA expression in the MNCs of urinary sediment of patients with subclinical borderline rejection. These results demonstrate that hRECs exposed to IL-17 can produce inflammatory mediators with the potential to stimulate early alloimmune responses, which may also serve to give warning of acute renal allograft rejection.
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The aim of this study was to: (a) analyze the results of a large-scale newborn screening program for Pompe disease, and (b) establish an effective diagnostic protocol to obtain immediate, valid diagnosis of infantile-onset Pompe disease (IOPD) to promote earlier treatment and better outcomes. In this study, 402,281 newborns were screened for Pompe disease from January 1, 2008 to May 1, 2012. Infants with low acid α-glucosidase (GAA) activity were referred to Taipei Veterans General Hospital for diagnostic confirmation. Physical examination, biochemical parameter (creatine kinase [CK], alanine transaminase, aspartate aminotransferase, and lactate dehydrogenase), and echocardiogram assessments were performed immediately to effectively differentiate IOPD from suspected late-onset Pompe disease (LOPD) or false-positive cases with pseudodeficiency mutation. Six infants with IOPD all presented with hypotonia, extremely low GAA enzyme activity (≤0.5 µmol/L/hr) in initial dried blood spot analysis, high CK (≥250 U/L), and high left ventricular mass index (LVMI, ≥80 g/m(2)). By analyzing these parameters, IOPD was distinguished effectively and immediately from suspected LOPD and false-positive cases. Except for the first referred case, five of the infants with IOPD received first-time enzyme replacement therapy (ERT) within 4 hr of admission and exhibited marked improvement. Our findings indicate that certain clinical manifestations (hypotonia, high CK, enlarged LVMI, and extremely low GAA enzyme activity in initial dried blood spot analysis) can help in the rapid and effective differentiation of patients with IOPD from other patient with low GAA activity. Such differentiation allows for the early application of first-time ERT and leads to better outcomes.
Forty-one out of 408 cases (or 10%) of primary glomerular disease had diffuse fine granular to arc-like short linear mesangial deposits of IgM by direct immunofluorescence. The IgM deposition was accompanied by C1q and/or C4 in the same locality in 29 cases, by C3 in 10, and by trace amounts of IgA in 6. Properdin-factor B was not detected. Fine granular electron dense deposits of low density were detected in the mesangium in all 41 cases by electron microscopy, usually as a discrete granular or arc-like pattern beneath the mesangial glomerular basement membrane and correlated well with the immunofluorescence findings. An immune complex disease with complement activation via the classical pathway is suggested. The ages of the patients varied from 2 to 58 years (average 23.8 years). A male predominance of 2.2:1 was identified. Serum IgM level was elevated in 46.7% of the cases. The majority (87.8%) of the cases manifested a nephrotic syndrome or relapse at time of biopsy, and the remaining cases experienced persistent or intermittent proteinuria. Among the 36 nephrotic patients, 22 cases (61.1%) demonstrated complete remission with steroid therapy, 9 cases (25%) were resistant, and 5 cases (13.9%) had partial remission. Complete and partial remissions were later achieved with cytotoxic drugs or methylprednisolone pulse therapy in 3 and 4 cases respectively in the steroid resistant patients. Frequent relapses occurred during the course in 22 out of 32 cases (68.8%) who had experienced complete or partial remission. Follow-up study after biopsy demonstrated that sustained complete remission was achieved with prednisolone with or without cytotoxic drugs and pulse therapy in only 14 (42.4%) of the 33 nephrotic cases who had been followed up for longer than 6 months, and six of them had had previous relapses. Pathologically, 56.1% of the patients showed mild to moderate increase in mesangial matrix and cellularity. Focal and segmental sclerosis was demonstrated in four cases (9.8%). However, minimal glomerular change was also common (34.1%). The patients with minimal change seemed to have a higher complete remission rate than patients with more evident glomerular alterations, although the difference was not statistically significant. This clinical and immunopathological study suggests that mesangial IgM nephropathy is an important disease in Taiwan, with a variable response to treatment and frequent relapses.(ABSTRACT TRUNCATED AT 400 WORDS)
Nitric oxide (NO) deficiency is associated with development of hypertension. We examined whether melatonin protects against the blood pressure increase is because of the restoration of the NO pathway. Spontaneous hypertensive rats (SHR) and control normotensive Wistar Kyoto (WKY) rats aged 4 weeks were assigned to four groups (N=6 for each group): untreated SHR and WKY, melatonin-treated SHR and WKY. Melatonin-treated rats received 0.01% melatonin in drinking water for 8 wks. All rats were sacrificed at 12 wk of age. SHR had higher blood pressure than WKY, which melatonin prevented. Plasma asymmetric dimethylarginine (ADMA) levels were elevated in SHR, combined with a reduction in plasma L-arginine to ADMA ratio (AAR). In the kidney, L-arginine, ADMA, and AAR were not different between SHR and WKY rats, whereas L-citrulline level was increased in SHR. Melatonin decreased plasma ADMA level and restored plasma AAR. Renal dimethylarginine dimethylaminohydrolase (DDAH, ADMA-metabolizing enzyme) activity was lower in SHR than WKY rats, which melatonin therapy prevented. Also, melatonin elevated both L-arginine and ADMA but reduced L-citrulline level in the kidney in SHR, which was associated with the prevention of reduced renal argininosuccinate lyase (ASL) expression in SHR. Moreover, melatonin reduced the degree of oxidative damaged DNA product, 8- hydroxydeoxyguanosine (8-OHdG) immunostaining in SHR. The observed antihypertensive effects of melatonin in young SHR are because of the restoration of the NO pathway by reduction of plasma ADMA, restoration of plasma AAR, preservation of renal L-Arg availability, and attenuation of oxidative stress.
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