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Biomedical subjects

Jun Wada

Publications and source records attributed to Jun Wada.

At least 55 records · Page 3Linked to original sources

Pelvic lymphocyst infection associated with maternally inherited diabetes mellitus.

A 45-year-old woman with 20-year history of diabetes mellitus was admitted to our hospital because of high fever and abdominal pain. Radical hysterectomy and bilateral pelvic lymphadenectomy had been performed 4 months before admission for invasive cervical cancer. On admission, elastic hard tumors were palpable in the lower abdomen. Laboratory examination showed positive C-reactive protein (CRP), anemia and renal dysfunction. Computed tomography (CT) revealed several lymphocysts in the pelvis. She was diagnosed with infection of pelvic lymphocysts. Since her mother also had diabetes associated with deafness, we examined mitochondrial DNA in leukocytes and detected an A to G transition at the nucleotide position of 3243 (A3243G mutation). She was diagnosed as maternally inherited diabetes mellitus and deafness (MIDD). Puncture of the cysts followed by administration of antibiotics resulted in marked improvement of symptoms and laboratory findings. This is a rare case of pelvic lymphocyst infection in a patient with a mitochondrial disorder. Although the exact mechanism of infection is not clear, MIDD may represent an unusual risk factor for infection, and further investigation is necessary to assess the influence of mitochondrial dysfunction on the immune system. Pelvic lymphocyst infection should be considered in the differential diagnosis of abdominal pain and fever in patients with MIDD after abdominal surgery.

Abdominal Pain↗

Daily exercise lowers blood pressure and reduces visceral adipose tissue areas in overweight Japanese men.

OBJECTIVE: To investigate the link between a reduction in blood pressure (BP) and daily exercise. DESIGN: Cross-sectional and longitudinal clinical intervention study with exercise education. SUBJECTS: 43 overweight Japanese men aged 32-59 years (BMI, 29.0+/-2.3 kg/m2) at baseline. Among the participants, a randomly selected 23 overweight men (BMI, 28.5+/-1.7) were further enrolled into the 10 months exercise program. MEASUREMENTS: BP was measured every week and steps per day were also recorded every day throughout the observation period. Fat distribution was evaluated by visceral fat (V) and subcutaneous fat (S) areas measured with computed tomography (CT) scanning at umbilical level, at before, 5 months and after intervention. Anthropometric parameters were also measured at same point. Aerobic exercise level, muscle strength, flexibility and calorie intake and insulin resistance (HOMA index) were investigated at before and after the study. RESULTS: In a cross sectional analysis, systolic BP (SBP) and diastolic BP (DBP) were significantly correlated with body composition. In a second longitudinal analysis, SBP was significantly reduced at 2 months and DBP was also reduced at 3 months, and almost maintained until the end of the observation period. Increasing daily walking was observed in 3 months and maintained until 10 months. Body composition, aerobic exercise level, muscle strength, flexibility and insulin resistance were significantly improved. There was positive correlation between DeltaDBP and Deltavisceral fat area (1-5, 5-10, 1-10 months). By stepwise multiple regression analysis, only Deltavisceral fat area was independently related to DeltaDBP at a significant level (1-10 months: DeltaDBP=-0.608+0.105Deltavisceral fat area, r2=0.227, P=0.0334). CONCLUSION: The present study indicated daily exercise lowers BP and visceral fat area is the critical factor for BP change.

Adipose Tissue↗

Imprinted mesodermal specific transcript (MEST) and H19 genes in renal development and diabetes.

BACKGROUND: Imprinted genes, mesodermal specific cDNA or transcript (MEST) and H19, are implicated in peri-implantation embryogenesis, and their expression was assessed in embryonic kidneys undergoing glucose-induced dysmorphogenesis. METHODS: MEST and H19 mRNA expression was assessed by Northern blot analysis in embryonic kidneys of mice harvested at day 15 to day 19 of gestation and of 1-week-old mice obtained from hyperglycemic mothers. A full-length mouse MEST cDNA was isolated, subcloned into an expression vector, a recombinant protein prepared and an antibody raised; the latter was used to assess protein expression by immunoprecipitation and immunofluorescence microscopy in day 13 metanephric explants subjected to high glucose ambience. Also, MEST mRNA expression was assessed in high d glucose-treated explants by competitive reverse transcription-polymerase chain reaction (RT-PCR) analyses and by in situ tissue autoradiography. RESULTS: A high expression of MEST and H19 with respective transcript size of approximately 2.7 and approximately 2.4 kb was observed in fetal kidneys, and their expression decreased during the successive stages of gestation and was undetectable in the postnatal period. At day 13, the MEST mRNA was expressed in the mesenchyme, while H19 was expressed in the ureteric bud branches and epithelial elements of the metanephros. Their expression decreased with progression of gestation. By competitive RT-PCR and Northern blot and in situ autoradiographic analyses, both MEST and H19 expressions decreased in day 13 explants treated with high glucose and in the kidneys of fetuses obtained from diabetic mothers. The MEST protein expression was observed in the metanephric epithelial elements and ureteric bud branches instead of in the mesenchyme, and its expression decreased in glucose-treated dysmorphogenetic explants, as assessed by immunofluorescence and immunoprecipitation methods. CONCLUSION: MEST and H19 imprinted genes are strategically located in the mammalian embryonic metanephros. They are developmentally regulated and their concomitant decreased expression in high glucose ambience or diabetic state did not follow the prevailing dogma of reciprocal inactivation/activation of imprinted genes, and such a decrease may be responsible for the perturbed epithelial:mesenchymal interactions leading to dysmorphogenesis of the mammalian metanephros.

Animals↗

Perturbation of autocrine/paracrine loops of burst-forming units of erythroid-derived cells in rHuEPO-hyporesponsive hemodialysis patients.

BACKGROUND: Quantitative or qualitative abnormalities of erythroid progenitors in patients with chronic renal failure (CRF) could be the major factor for recombinant human erythropoietin (rHuEPO) hyporesponsiveness and severe anemia in hemodialysis (HD) patients receiving rHuEPO therapy. METHODS: Purified 1 x 10(4) circulating CD34+ cells isolated from rHuEPO-hyporesponsive HD patients (EPO-H; n = 10), rHuEPO-responsive non-HD patients with CRF (EPO-R; n = 8), nonanemic HD patients without rHuEPO therapy (EPO-W/O; n = 10), and healthy volunteer controls (CON; n = 10) were subjected to a methylcellulose culture system supplemented with rHuEPO, recombinant human interleukin-3 (IL-3), recombinant human stem cell factor (SCF), and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) for 14 days. RESULTS: The average number of burst-forming units of erythroids (BFU-Es) was significantly less in the EPO-H group compared with the CON and EPO-W/O groups. Furthermore, colony size also was significantly smaller in the EPO-H group. Total RNAs were extracted from approximately 100 colonies/patient and subjected to complementary DNA expression array studies of 268 growth factors, cytokines, chemokines, and their receptors. A characteristic cluster upregulated in the EPO-R and EPO-W/O groups and downregulated in the EPO-H group was identified that contained various cytokines and growth factors, including IL-6, GM-CSF, vascular endothelial growth factor B, IL-9, IL-3, leukemia inhibitory factor, and interferon alpha-2, and such receptors as thrombopoietin receptor, IL-9 receptor, and colony-stimulating factor 1 receptor. CONCLUSION: These data suggest that the cross-talk network or autocrine/paracrine regulatory loop is critically impaired in BFU-E-derived cells in EPO-H patients, and investigation of these cluster genes would facilitate the development of novel therapeutic strategies for such patients.

Aged↗

Pathogenesis of IgA nephropathy.

Immunoglobulin A (IgA) nephropathy is an immune-complex-mediated glomerulonephritis characterized by the presence of immunoglobulin A deposits in mesangial and paramesangial regions. The patients with IgA nephropathy present with varying clinical symptoms (eg, microhematuria with preserved renal function or progressive deterioration of renal functions resulting in end-stage renal disease). The factors involved in the pathogenetic mechanisms of IgA nephropathy include (1). environmental factors, (2). genetic factors, (3). abnormality of the IgA1 molecule, and (4). various inflammatory mediators. The gene polymorphism studies for human leukocyte antigen (HLA), renin-angiotensin-aldosterone system, and selectin gene clusters, suggest a certain degree of genetic predisposition in patients for IgA nephropathy. Also, the genome-wide screening in familial IgA nephropathy showed linkage of IgA nephropathy to the 6q22-23 chromosome. Besides genetic influence in its pathogenesis, aberrant galactosylation in serum IgA and IgA1 eluted from kidneys with IgA nephropathy has been observed, and conceivably such abnormalities induce the expression of various cytokines, interleukin (IL)-6, platelet-derived growth factor (PDGF), tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta1 in the renal cells, which contributes to further glomerular injury. Despite an enormous amount of information available in the literature, further studies are needed to delineate the precise pathogenetic mechanisms involved in primary IgA nephropathy and also to facilitate the development of newer therapeutic interventions.

Animals↗

HMG-CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats.

BACKGROUND: An inflammatory process may be one of the critical factors that contribute to the development of diabetic nephropathy (DN). We reported previously that intercellular adhesion molecule-1 (ICAM-1) is up-regulated and promotes macrophage infiltration in the glomeruli of diabetic rats. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have recently been emphasized to have anti-inflammatory effects; inhibition of leukocyte adhesion and migration, independent of the cholesterol-lowering effect. The present study was designed to test the hypothesis that statins prevent the development of DN by pleiotropic effects. METHODS: Streptozotocin-induced diabetic rats were treated with cerivastatin (0.5 mg/kg body weight) or vehicle for 4 weeks. We analysed glomerular macrophage infiltration and ICAM-1 expression. We also evaluated major regulators of ICAM-1, activation of nuclear factor-kappa B (NF-kappaB) using electrophoretic mobility shift assay, and oxidative stress. RESULTS: Statin treatment reduced urinary albumin excretion (UAE) (2.96+/-0.18 vs 2.38+/-0.06; log(10) UAE, P<0.05), glomerular size (12 150+/-329 vs 9963+/-307 micro m(2), P<0.05), and lowered blood pressure, compared with untreated diabetic rats. Immunohistochemistry revealed that macrophage infiltration and ICAM-1 expression in glomeruli were increased in diabetic rats and were inhibited by statin treatment. Renal NF-kappaB activity, urinary excretion and renal deposition of 8-OHdG were increased in diabetic rats, and reduced by statin treatment. CONCLUSION: Statin treatment prevented glomerular injury, independent of the cholesterol-lowering effects. Our findings suggest that the beneficial effect might be mediated by pleiotropic effects including an anti-inflammatory action through a reduction of oxidative stress, NF-kappaB activation, ICAM-1 expression and macrophage infiltration in the early phase of DN.

8-Hydroxy-2'-Deoxyguanosine↗

Remission and regression of diabetic nephropathy.

Diabetic nephropathy has become the single largest cause of end-stage renal disease (ESRD) worldwide. Until recently, it was thought that once a patient developed overt proteinuria, diabetic nephropathy was irreversible and inevitably progressed to ESRD. However, the reversal of lesions caused by diabetic nephropathy (e.g., glomerular basement membrane thickening and mesangial matrix increase) has been demonstrated in a series of patients who underwent a pancreas transplantation 10 years prior to the reversal. Remission of nephrotic range proteinuria has also been reported in some patients with type 1 diabetes from the Collaborative Study Group during a median follow-up of 3 years of angiotensin-converting enzyme (ACE) inhibitor administration; no deterioration of renal function was observed in these patients. Remission and regression in nephropathy of type 1 diabetes patients have also been reported when blood pressure was controlled aggressively. Recent clinical trials have demonstrated that angiotensin II receptor blocker (ARB) preserved renal function and slowed the progression of nephropathy to ESRD in patients with type 2 diabetes. Since many patients with type 2 diabetes manifest with a metabolic syndrome, multifactorial intensive treatment is necessary; such treatment includes behavior modifications, dietary intervention, exercise, and smoking cessation. In this population, pharmacological therapy targeting hyperglycemia, hypertension (including ARB/ACE inhibitor), and hyperlipidemia in cases of type 2 diabetes is also necessary.

Angiotensin-Converting Enzyme Inhibitors↗

Gene regulation of aldose-, aldehyde- and a renal specific oxido reductase (RSOR) in the pathobiology of diabetes mellitus.

Aldose-, aldehyde and renal specific oxido reductase (RSOR) belong to the family of aldo-keto reductases (AKRs). They are monomeric (alpha/beta)8-barrel proteins with a molecular weight ranging from 30 to 40 kDa, and at present include more than 60 members. Except for RSOR, they are expressed in a wide variety of animal and plant species and in various tissues. They catalyze NADPH-dependent reduction of various aliphatic and aromatic aldehyde and ketones. During the past three decades aldehyde reductase (AKR1A) and aldose reductase (AKR1B) have been extensively investigated, and the gene regulation of AKR1B has been noted to be heavily influenced by hyperglycemic state and high glucose ambience in various culture systems. AKR1B catalyzes the conversion of glucose to sorbitol in concert with a coenzyme, NADPH. The newly discovered RSOR has certain structural and functional similarities to AKR1B and seems to be relevant to the renal complications of diabetes mellitus. Like other AKRs, it has a NADPH binding motif, however, it is located at the N-terminus and it probably undergoes N-linked glycosylation in order to achieve functional substrate specificity. Besides the AKR3 motif, it has very little nucleotide or protein sequence homology with other members of the AKR family. Nevertheless, gene regulation of RSOR, like AKR1B, is heavily modulated by carbonyl, oxidative and osmotic stresses, and thus it is anticipated that its discovery would lead to the development of new inhibitors as well as gene therapy targets to alleviate the complications of diabetes mellitus in the future.

Aldehyde Reductase↗

Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes.

Diabetic nephropathy is a leading cause of end-stage renal failure. Several mechanisms, including activation of protein kinase C, advanced glycation end products, and overexpression of transforming growth factor (TGF)-beta, are believed to be involved in the pathogenesis of diabetic nephropathy. However, the significance of inflammatory processes in the pathogenesis of diabetic microvascular complications is poorly understood. Accumulation of macrophages and overexpression of leukocyte adhesion molecules and chemokines are prominent in diabetic human kidney tissues. We previously demonstrated that intercellular adhesion molecule (ICAM)-1 mediates macrophage infiltration into the diabetic kidney. In the present study, to investigate the role of ICAM-1 in diabetic nephropathy, we induced diabetes in ICAM-1-deficient (ICAM-1(-/-)) mice and ICAM-1(+/+) mice with streptozotocin and examined the renal pathology over a period of 6 months. The infiltration of macrophages was markedly suppressed in diabetic ICAM-1(-/-) mice compared with that of ICAM-1(+/+) mice. Urinary albumin excretion, glomerular hypertrophy, and mesangial matrix expansion were significantly lower in diabetic ICAM-1(-/-) mice than in diabetic ICAM-1(+/+) mice. Moreover, expressions of TGF-beta and type IV collagen in glomeruli were also suppressed in diabetic ICAM-1(-/-) mice. These results suggest that ICAM-1 is critically involved in the pathogenesis of diabetic nephropathy.

Albuminuria↗

Evaluation of exercise prescription for hypertensive obese men by ventilatory threshold.

BACKGROUND: Prescription of aerobic exercise for obese subjects with mild hypertension in clinical practice remains to be investigated. METHODS: Forty-one Japanese obese males with hypertension were enrolled and compared with 41 age-and sex-matched obese subjects without hypertension and control subjects. In addition, 25 obese subjects with or without hypertension participated in a one-year follow up study. They were instructed to keep their low exercise intensity and record their daily walking. Before and after exercise prescription, body composition, blood pressure and aerobic exercise level were evaluated. Ventilatory threshold (VT) was determined breath by breath during exercise test using a ramp protocol and rates of oxygen consumption (VO2), work rate (WR), heart rate (HR), deltaHR, %HR max, %HR reserve and rate of perceived exertion (RPE) were measured at VT. RESULTS: At VT, obese subjects with hypertension had significantly lower VO2 (13.5 +/- 2.1 mL/kg/min) and WR (75.1 +/- 16.5W) than control subjects (VO2, 18.1 +/- 5.7; WR, 92.0 +/- 32.4). %HR reserve was also significantly lower compared with control subjects, while %HR max, was not different. RPE was also similar among the 3 groups. By prescribed low-grade exercise during one-year follow-up study, not only body composition but also blood pressure at rest was improved in obese subjects with and without hypertension. CONCLUSIONS: Our results indicated reduced exercise capacity in Japanese obese males. Exercise intensity of 60%HR max, 30%HR reserve and RPE 12 is recommended in obese subjects with hypertension as well as obese subjects without hypertension.

Adult↗

Isolation and functional analysis of mouse UbA52 gene and its relevance to diabetic nephropathy.

In delineating the mechanism(s) of diabetic nephropathy various novel genes have been isolated, whereas others remain to be discovered. We identified several up-regulated genes in the kidneys of diabetic newborn mice. Among them was UbA52, a ubiquitin ribosomal fusion protein. Its mRNA expression in the kidney was proportional to blood glucose levels. By in situ hybridization and immunohistochemistry, UbA52 was exclusively localized to renal tubules, and its expression was markedly increased in diabetic mice. The up-regulated UbA52 mRNA and protein expression were also observed in Madin-Darby canine kidney cells, a tubular cell line, treated with 30 mm glucose in both cell lysates and ribosomal fractions. To explore the mechanism(s) of its increased expression, UbA52 genomic DNA was isolated. A transcription start site at -22 bp from the initiation codon was identified and confirmed by primer extension analysis. The UbA52 promoter region included glucose response-related E-box sequences and stress response elements (STRE). Unlike in humans, mouse UbA52 gene had no introns in the coding or 5'-ATG-flanking regions. To identify the DNA segment with maximal promoter activity, deletion constructs were prepared using a pSEAP vector system and transfected into COS7 kidney cells. Maximal activity was confined to -198 to +68 bp, which included E-boxes and STRE motifs. A dose-dependent increase in the promoter activity was observed in cells exposed to high glucose. Mutations in the first E-box (CAGCTG --> TGGCTG) or STRE (CCCCT --> CATCT) resulted in a decrease in the SEAP activity under high glucose ambience. Given the presence of glucose-responsive motifs in the promoter region and decrease in the SEAP activity in E-box mutants in the presence of glucose, these data suggest that UbA52, a ribosomal fusion protein, may be relevant in the pathogenesis of diabetic nephropathy.

Animals↗

Therapeutic effect of sulphated hyaluronic acid, a potential selectin-blocking agent, on experimental progressive mesangial proliferative glomerulonephritis.

The initial event in the process of leukocyte infiltration is characterized by leukocyte rolling on the surface of the endothelium, which is mediated by selectins. P- and L-selectin bind to the sulphated sugar chains of their natural ligands, including sulphated glycolipids such as sulphatide. Recently, it has been demonstrated that sulphated glycolipids and sulphated oligosaccharides interfere with selectin binding pathways. This study synthesized sulphated hyaluronic acid (SHA), which is a potential selectin-blocking agent, and examined its therapeutic effect on the experimental progressive mesangial proliferative glomerulonephritis induced by anti-Thy-1 monoclonal antibody (1-22-3 MAb) after unilateral nephrectomy. The selectin-inhibitory effect of SHA in vitro was confirmed. SHA inhibited the binding of P- and L-selectin to sulphatide, which is a glycolipid ligand for P- and L-selectin, at a concentration of 1.5 micro g/ml and 100 micro g/ml. Immunohistochemical examination showed that P-selectin was up-regulated in the glomeruli in the 1-22-3 MAb nephritis model, while the ligands for L-selectin were not detected in the glomerular tufts. A single administration of SHA ameliorated proteinuria and glomerular leukocyte infiltration in 24 h after the injection of anti-Thy-1 MAb. Anti-P-selectin MAb, but not anti-L-selectin MAb, inhibited proteinuria and glomerular leukocyte infiltration. To examine further the therapeutic effect of SHA on chronic glomerulonephritis, SHA was administered daily from day 3 to day 14 in this model. Proteinuria and glomerular leukocyte infiltration were significantly diminished in SHA-treated rats on day 14. These results suggest that SHA ameliorated rat progressive mesangial proliferative glomerulonephritis by inhibiting P-selectin-dependent leukocyte infiltration in glomeruli. Sulphated oligosaccharides may be beneficial for the therapy of mesangial proliferative glomerulonephritis.

Animals↗

Beraprost sodium, prostacyclin analogue, attenuates glomerular hyperfiltration and glomerular macrophage infiltration by modulating ecNOS expression in diabetic rats.

Stable prostacyclin analogue, beraprost sodium (BPS) has recently been reported to attenuate glomerular hyperfiltration in diabetic rats, however, the mechanism has been still unknown. We previously reported that overexpression of endothelial cell nitric oxide synthase (ecNOS) in afferent arterioles and glomeruli induce inappropriate dilatation of afferent arterioles and glomerular hyperfiltration through overproduction of nitric oxide in early stage of diabetic nephropathy. In this study, we tested the hypothesis that BPS ameliorates glomerular hyperfiltration through modulating ecNOS expression in diabetic nephropathy. Furthermore, we examined the effects of BPS on the expression of intercellular adhesion molecule-1 (ICAM-1) and macrophage infiltration in diabetic glomeruli, because glomerular hyperfiltration induces the expression of ICAM-1 resulting in macrophage infiltration. Male Sprague-Dawley (SD) rats were administered continuously with BPS for 4 weeks after induction of diabetes by streptozotocin. In diabetic rats, the diameters of afferent arterioles, glomerular volume, creatinine clearance and urinary excretion of albumin and NO2/NO3 were increased as compared with non-diabetic control rats. Treatment with BPS improved these changes. The expression of ecNOS was increased in afferent arterioles and glomeruli in diabetic rats and suppressed by BPS. Prostacyclin receptor was expressed along afferent arterioles. Our results suggest that BPS attenuates glomerular hyperfiltration by modulating ecNOS expression in early stage of diabetic nephropathy. Moreover, BPS may inhibit ICAM-1-dependent infiltration of macrophages in diabetic glomeruli.

Animals↗

Daily walking reduces visceral adipose tissue areas and improves insulin resistance in Japanese obese subjects.

OBJECTIVE: It is known that the accumulation of abdominal fat is one of the risk factors for atherosclerosis. Although exercise is commonly prescribed to reduce body weight, the efficacy of low intensity exercise for the reduction of abdominal visceral adipose tissue remains to be investigated. RESEARCH DESIGN AND METHODS: Thirty one obese Japanese males (body mass index (BMI) > or = 25) ranging in age from 32 to 59, participated in a 1-year follow up study and they were instructed to have a modest increase in daily activity and record their daily walking. Before and after exercise prescription, body composition, blood pressure, physical fitness i.e. aerobic exercise level, muscle strength and flexibility were recorded. Insulin resistance was evaluated using a homeostasis model assessment, the HOMA index. RESULTS: HOMA index, parameters of body composition, blood pressure, triglyceride and HDL cholesterol were significantly improved. The aerobic exercise level, leg strength, weight-bearing index (leg strength/body weight) and the steps taken per day were significantly increased. By stepwise multiple regression analysis, Delta visceral adipose tissue area was the major determinant for Delta HOMA index. (Delta HOMA index=-0.386+0.016 Delta visceral adipose tissue area, r2=0.267, P<0.01). Exercise capacity and calorie intake were not significantly related to Delta visceral adipose tissue area, while Delta steps per day was significantly correlated with Delta visceral adipose tissue area (Delta visceral adipose tissue area=-21.363-0.004 Delta steps per day, r2=0.184, P=0.0326). CONCLUSIONS: Taken together, intra-abdominal visceral adipose tissue is critically involved in insulin resistance and daily walking rather than improvement of exercise capacity correlated with the reduction of visceral adipose tissue in obese Japanese males.

Activities of Daily Living↗

Gene expression and identification of gene therapy targets in diabetic nephropathy.

A number of novel genes that are up-regulated in diabetic kidneys have been identified. Recently, transforming growth factor-beta (TGF-beta)--driven secreted proteins, i.e., connective tissue growth factor (CTGF) and gremlin, were identified. They are up-regulated in kidneys of diabetic animals and modulate the biology of mesangial cells. CTGF mediates TGF-beta--induced matrix overproduction by the mesangial cells. Gremlin is a putative antagonist of bone morphogenetic protein-2 that blocks mesangial cell proliferation. Thus, gremlin may modulate the biology of mesangium by stimulating mesangial cell proliferation and in turn production of matrix. In addition, transcriptionally regulated kinases, serum glucocorticoid-regulated kinase and munc-13 have been identified. The former stimulates renal tubular Na+ transport and is involved in hyperfiltraion of diabetic kidneys by a Na+ transport feedback mechanism. Munc-13 has been shown to induce apoptosis in hyperglycemic state via diacylglycerol-activated, PKC-independent signaling pathway. Another pathway relevant to diabetic nephropathy is polyol pathway, where glucose is reduced to sorbitol by aldose reductase. Recently, a renal-specific reductase of the aldo-keto reductase family was isolated. It is up-regulated in diabetic mice, and this could serve as a suitable target for gene therapy in renal complications of diabetes. Several mitochondrial genome-encoded genes, such as, cytochrome oxidase and NADH dehydrogenase, are up-regulated in diabetic kidneys. A novel nuclear-encoded mitochondrial gene, i.e., translocase inner mitochondrial membrane 44 (Tim44), is up-regulated in diabetic kidneys, and it may also serve as another target for molecular therapeutic intervention at the core storage energy sites, i.e., mitochondria. In this review, these novel differentially regulated genes that respond to hyperglycemic stress are described, and they may serve as possible targets for gene therapy in the treatment of diabetic nephropathy.

Diabetic Nephropathies↗

Angiocentric immunoproliferative lesions of the lung associated with diffuse renal involvement.

A 62-year-old Japanese man presented with high fever, cough, and sputa. Computed tomography (CT) scan of the chest revealed lung infiltrates with air bronchogram of the right middle lobe and mediastinal lymphadenopathy. Bronchoscopic examination was performed, and Mycobacterium avium complex was detected from bronchoalveolar lavage fluid. Although the administration of clarithromycin and levofloxacin improved the patient's symptoms, the lung infiltrates on chest CT scan gradually worsened. Lung biopsy of segments 4 and 8 by video-assisted thorachoscopy revealed angiocentric and angiodestructive massive lymphoplasmocytic infiltrations with multinucleated giant cells, which were compatible with grade II angiocentric immunoproliferative lesions. The patient was found to have deterioration of renal function, and glomerular filtration rate was 32.6 mL/min. His kidneys were enlarged and showed prominent and diffuse uptake of gallium-67 citrate. Percutaneous renal biopsy revealed massive infiltration of CD4+ mononuclear cells, plasma cells, and eosinophils in the interstitium and destruction of normal structure of tubules. Blood vessels were destroyed and replaced by inflammatory cells. The combination chemotherapy achieved a remission, and the patient has remained free of disease at 2 years after onset of the illness. We recommend the imaging of kidneys for diagnosis and following renal biopsy to evaluate the renal involvement of angiocentric immunoproliferative lesions.

Biopsy↗