Increased frequency of surface IgA-positive plasma cells in the intestinal lamina propria and decreased IgA excretion in hyper IgA (HIGA) mice, a murine model of IgA nephropathy with hyperserum IgA

Because abnormalities of mucosal immunity have been suggested in human IgA nephropathy, we examined the involvement of mucosal immunity in IgA deposition to the kidney in hyper IgA (HIGA) mice, which was established as a mouse model for human IgA nephropathy with hyperserum IgA. The number of surface IgA+B220- lymphocytes in the intestinal lamina propria (LP) of HIGA mice increased 2.7-fold at 30 wk of age as compared with those at 10 wk of age, whereas normal mice did not show such increase. The surface IgA+B220- LP lymphocytes spontaneously secreted IgA in culture. Morphological studies showed that the surface IgA+B220- lymphocytes of murine intestinal LP are identical with plasma cells (PCs). About 20% of IgA+B220- PC in LP expressed both Mac-1 and CD19, suggesting that they may derive from peritoneal B-1 cells. Cell cycle study on intestinal IgA-PCs using bromodeoxyuridine revealed no difference between HIGA mice and normal mice, suggesting that the high frequency of IgA-producing PCs in HIGA mice is not due to enhanced proliferation or prolonged survival of IgA-producing PCs in LP. In addition, IgA secretion into the gut lumen of HIGA mice decreased drastically (to one forth) with aging. These data suggest that the increased number of intestinal IgA-producing PCs and the down-regulation of IgA excretion into the intestinal lumen might synergistically contribute to the hyperserum IgA in HIGA mice and resultant IgA deposition to the kidney.     

Possible role of NO modulators in protective effect of trazodone and citalopram (antidepressants) in acute immobilization stress in mice

Stress is an aversive stimulus which disturbs physiological homeostasis and is reflected on a variety of biological systems. The present study was designed to investigate the nitric oxide mechanism in neuroprotective effect of trazodone and citalopram against acute immobilization-induced behavioral and biochemical alteration in mice. Mice were immobilized for a 6 h. Acute immobilization stress caused anxiety, hyperalgesia, impaired locomotor activity and oxidative damage. Pretreatment with trazodone and citalopram significantly reversed immobilized stress-induced behavioral and biochemical alterations. L-arginine, pretreatment with trazodone or citalopram significantly reversed their protective effects. However, L-NAME or methylene blue pretreatment with trazodone or citalopram significantly potentiated their protective effects alone. Results suggest the involvement of nitric oxide pathways in the protective effect of trazodone and citalopram against immobilization stress induced behavioral and biochemical alterations.     

蝉花虫草提取物N~6-(2-羟乙基)腺苷对小鼠肾脏缺血再灌注损伤的保护作用

研究蝉花虫草提取物N~6-(2-羟乙基)腺苷[N~6-(2-hydroxyethyl)-adenosine,HEA]对小鼠肾脏缺血再灌注损伤(ischemia reperfusion,IR)的影响。选择20–25g雄性C57BL/6小鼠,随机分成5组。假手术组小鼠仅接受腹中线开腹、游离双侧肾蒂及缝合腹部操作;IR组小鼠制成肾脏IR模型,不给药;HEA低剂量组、HEA中剂量组、HEA高剂量组分别在建立肾脏缺血再灌注模型前15min腹腔注射HEA(2.5mg/kg、5mg/kg和7.5mg/kg)。再灌注24h后检测各组肾功能指标血清肌酐(serum creatinine,Scr)和尿素氮(blood urea nitrogen,BUN)水平。苏木精-伊红染色后用光学显微镜观察肾脏组织形态学改变。电镜和TUNEL分析法观察肾小管上皮细胞凋亡状况。实时荧光定量RT-PCR检测细胞间粘附分子-1(intercellular adhesion molecule-1,ICAM-1)、白细胞介素(interleukin-1β,IL-1β)和肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)等基因的m RNA的表达情况。结果显示,与假手术组比较,IR组BUN和Scr水平明显升高(P0.01,P0.05);肾脏病理表现为上皮细胞碎片和管型,且最为严重;与IR组比较,HEA 7.5mg/kg组血清BUN和Scr水平显著降低(P0.05);HEA 5mg/kg组和HEA 7.5mg/kg组肾损伤情况明显改善(P0.05,P0.01);电镜观察可知HEA 7.5mg/kg组明显改善肾小管上皮细胞的损伤程度,并且保护线粒体和细胞核膜的完整性。原位末端标记法[terminal dexynucleotidyl transferase(Td T)-mediated d UTP nick end labeling,TUNEL]显示HEA治疗组凋亡细胞数量明显低于IR组(P0.01)。HEA治疗组ICAM-1、IL-1β和TNF-αm RNA的水平均低于IR组(P0.01)。所以预处理HEA 7.5mg/kg对肾脏缺血再灌注有保护作用。     

Targeted deletion of the IgA constant region in mice leads to IgA deficiency with alterations in expression of other Ig isotypes

A murine model of IgA deficiency has been established by targeted deletion of the IgA switch and constant regions in embryonic stem cells. B cells from IgA-deficient mice were incapable of producing IgA in vitro in response to TGF-beta. IgA-deficient mice expressed higher levels of IgM and IgG in serum and gastrointestinal secretions and decreased levels of IgE in serum and pulmonary secretions. Expression of IgG subclasses was complex, with the most consistent finding being an increase in IgG2b and a decrease in IgG3 in serum and secretions. No detectable IgA Abs were observed following mucosal immunization against influenza; however, compared with those in wild-type mice, increased levels of IgM Abs were seen in both serum and secretions. Development of lymphoid tissues as well as T and B lymphocyte function appeared normal otherwise. Peyer's patches in IgA-deficient mice were well developed with prominent germinal centers despite the absence of IgA in these germinal centers or intestinal lamina propria. Lymphocytes from IgA-deficient mice responded to T and B cell mitogens comparable to those of wild-type mice, while T cells from IgA-deficient mice produced comparable levels of IFN-gamma and IL-4 mRNA and protein. In conclusion, mice with targeted deletion of the IgA switch and constant regions are completely deficient in IgA and exhibit altered expression of other Ig isotypes, notably IgM, IgG2b, IgG3, and IgE, but otherwise have normal lymphocyte development, proliferative responses, and cytokine production.     

Metabolic disorders of serum lipoproteins in endotoxin-poisoned mice: the role of high density lipoprotein (HDL) and triglyceride-rich lipoproteins

A study was performed to clarify the role of serum lipoproteins, especially high density lipoprotein (HDL) and triglyceride-rich lipoproteins in endotoxemic or endotoxin-poisoned animals. The level of HDL-cholesterol decreased markedly in mouse serum 18-24 hr postintoxication, while the amount of low density lipoprotein (LDL)-cholesterol in the sera of poisoned mice was about 175% of that of the controls. Serum lecithin-cholesterol acyltransferase activity in the poisoned mice decreased slightly for 3-6 hr after endotoxin injection, but became markedly increased at 18-24 hr as compared with that in the controls. The amount of serum very low density lipoprotein (VLDL) showed a marked increase in the poisoned mice 8-24 hr postintoxication. The HDL fraction in the electrophoretic patterns of serum was reduced according to the dose of endotoxin 18 hr postintoxication. The HDL fraction in mice injected with lead acetate plus endotoxin was markedly lower than that in the poisoned mice. When streptozotocin-diabetic mice were injected with endotoxin, the HDL fraction was higher than that in the endotoxin-poisoned mice. In endotoxin-poisoned mice a correlation was observed between the lipid peroxide and LDL levels in the serum. In disk electrophoretic patterns, the HDL fraction in mice given vitamin E-supplemented diet showed a higher level than that in mice given a normal diet. Lipoprotein lipase (LPL) activity in poisoned mice significantly decreased to 59% of the control value 18 hr postintoxication, but hepatic triglyceride lipase activity was only slightly increased in endotoxin-poisoned mice. In analysis of HDL apoprotein peptide in serum lipoprotein, the apo C-II peptide level was clearly lower in mouse serum 18 hr postintoxication than that in the controls. These results suggest that the decrease in LPL activity in endotoxin-poisoned mice may be closely related to a decrease in the apo C-II peptide level, and also that it plays an important part in HDL and triglyceride-rich lipoprotein metabolism in the poisoned mice.     

Downregulated expression of integrin alpha6 by transforming growth factor-beta(1) on lens epithelial cells in vitro

Integrins represent the main cell surface receptors that mediate cell-matrix and cell-cell interactions. They play critical roles in adhesion, migration, morphogenesis, and the differentiation of several cell types. Previous studies have demonstrated that members of the fibroblast growth factor (FGF)-2, transforming growth factor (TGF)-beta(1), and insulin growth factor (IGF)-1 play important roles in lens biology. In particularly, TGF-beta(1) appears to play a key role in extracellular matrix production, cell proliferation, and cell differentiation of lens epithelial cells. In this study we investigated the effects of FGF-2, TGF-beta(1), and IGF-1 on the modulation of integrin receptors using lens epithelial cell lines (HLE B-3 and alphaTN-4) and lens explants. We found that the expression of integrin alpha6 is downregulated by TGF-beta(1), but is not responsive to FGF-2 or IGF-1. The promoter activity of the integrin alpha6 gene decreased upon TGF-beta(1) treatment in a transient transfection assay, and flow cytometric analysis demonstrated the reduced expression of integrin alpha6 by TGF-beta(1), whereas significant changes were not observed in the level of integrin alpha6 after the addition of FGF-2. These findings suggest that the reduced expression of integrin alpha6 caused by TGF-beta(1) might play a role in the activation of the cell cycle genes required during the fiber differentiation of the lens.     

The protective role of hydrophilic tetrahydroxylated bile acids (THBA)

Bile acids are key components of bile required for human health. In humans and mice, conditions of reduced bile flow, cholestasis, induce bile acid detoxification by producing tetrahydroxylated bile acids (THBA), more hydrophilic and less cytotoxic than the usual bile acids, which are typically di- or tri-hydroxylated. Mice deficient in the Bile Salt Export Pump (Bsep, or Abcb11), the primary bile acid transporter in liver cells, produce high levels of THBA, and avoid the severe liver damage typically seen in humans with BSEP deficiencies. THBA can suppress bile acid-induced liver damage in Mdr2-deficient mice, caused by their lack of phospholipids in bile exposing their biliary tracts to unbound bile acids. Here we review THBA-related works in both animals and humans, and discuss their potential relevance and applications as a class of functional bile acids.     

Proteomic identification of hippocalcin and its protective role in heatstroke-induced hypothalamic injury in mice

Heatstroke is a devastating condition that is characterized by severe hyperthermia and central nervous system dysfunction. However, the mechanism of thermoregulatory center dysfunction of the hypothalamus in heatstroke is unclear. In this study, we established a heatstroke mouse model and a heat-stressed neuronal cellular model on the pheochromocytoma-12 (PC12) cell line. These models revealed that HS promoted obvious neuronal injury in the hypothalamus, with high pathological scores. In addition, PC12 cell apoptosis was evident by decreased cell viability, increased caspase-3 activity, and high apoptosis rates. Furthermore, 14 differentially expressed proteins in the hypothalamus were analyzed by fluorescence two-dimensional difference gel electrophoresis and identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Expression changes in hippocalcin (HPAC), a downregulated neuron-specific calcium-binding protein, were confirmed in the hypothalamus of the heatstroke mice and heat-stressed PC12 cells by immunochemistry and western blot. Moreover, HPAC overexpression and HPAC-targeted small interfering RNA experiments revealed that HPAC functioned as an antiapoptotic protein in heat-stressed PC12 cells and hypothalamic injury. Lastly, ulinastatin (UTI), a cell-protective drug that is clinically used to treat patients with heatstroke, was used in vitro and in vivo to confirm the role of HPAC; UTI inhibited heat stress (HS)-induced downregulation of HPAC expression, protected hypothalamic neurons and PC12 cells from HS-induced apoptosis and increased heat tolerance in the heatstroke animals. In summary, our study has uncovered and demonstrated the protective role of HPAC in heatstroke-induced hypothalamic injury in mice.     

Drd2 expression in the high alcohol-preferring and low alcohol-preferring mice

The high alcohol-preferring (HAP) and low alcohol-preferring (LAP) mice were selectively bred for differences in alcohol preference and consumption. Recently, a large-effect QTL was identified on chromosome 9. The peak for this QTL is near the Drd2 (dopamine receptor 2) locus. The present study examined Drd2 mRNA expression differences between the HAP1 and LAP1 mice in brain regions important in the dopaminergic-reward pathway, including the nucleus accumbens, hippocampus, amygdala, and septum. Results show that alcohol-naïve HAP1 mice exhibited lower levels of Drd2 mRNA expression in the nucleus accumbens and the hippocampus compared to LAP1 mice. No differences were found in the amygdala or septum. To determine if a sequence difference might underlie the expression difference, the Drd2 cDNA was sequenced in each line and one single nucleotide polymorphism (SNP) was identified in the 3′ UTR. Both HAP and LAP 3′ UTR were cloned in the luc-pGL3-promoter-luc vector. The polymorphism in the Drd2 3′ UTR was assessed to determine its functional significance in modulating expression. In vitro expression analysis using neuroblastoma SK-N-SH cells resulted in a significant decrease in expression of the HAP 3′ UTR luc construct compared with the LAP 3′ UTR construct. This decreased expression is consistent with lower levels of Drd2 expression in the nucleus accumbens and the hippocampus as evidenced by qRT-PCR. These results suggest that the SNP may play a role in the differential expression of Drd2 between the HAP and LAP mice and that the polymorphism in Drd2 may contribute to alcohol preference.     

An emerging role of deubiquitinating enzyme cylindromatosis (CYLD) in the tubulointerstitial inflammation of IgA nephropathy

Immunoglobulin A (IgA) nephropathy is an important cause of end-stage kidney disease (ESKD). Tubulointerstitial inflammation and subsequent fibrosis appear to be a major contributor of the disease progression to ESKD; however, the underlying mechanism is poorly understood. Herein, we report that a unique feature of CYLD expression in kidneys of patients with IgA nephropathy and a CYLD-mediated negative regulation of inflammatory responses in human tubular epithelial cells. Immunochemical staining revealed that CYLD was predominantly expressed in renal tubular epithelial cells in 81% of the patients (37 cases) with proteinuric IgA nephropathy. Patients with positive CYLD had significantly less tubulointerstitial lesions and higher estimated glomerular filtration rate (eGFR) levels when compared with those negative. Logistic regression analysis indicated that eGFR was a predictor for the CYLD expression. In cultured human tubular epithelial HK-2 cells, tumor necrosis factor-alpha (TNFα) up-regulated CYLD expression. Adenoviral knockdown of CYLD did not affect albumin-, hydrogen peroxide (H₂O₂)-, tunicamycin- or thapsigargin-induced cell death; however, it enhanced TNFα-induced expression of intracellular adhesion molecule (ICAM)-1 as well as activation of c-Jun N-terminal kinase (JNK). Moreover, monocyte adhesion to the TNFα-inflamed HK-2 cells was significantly increased by the CYLD shRNA approach. Taken together, our results suggest that CYLD negatively regulates tubulointertitial inflammatory responses via suppressing activation of JNK in tubular epithelial cells, putatively attenuating the progressive tubulointerstitial lesions in IgA nephropathy.     

Metabolism and neurotoxicity of homocysteine thiolactone in mice: protective role of bleomycin hydrolase

Genetic or nutritional disorders in homocysteine (Hcy) metabolism elevate Hcy-thiolactone and cause heart and brain diseases. Hcy-thiolactone has been implicated in these diseases because it has the ability to modify protein lysine residues and generate toxic N-Hcy-proteins with auto-immunogenic, pro-thrombotic, and amyloidogenic properties. Bleomycin hydrolase (Blmh) has the ability to hydrolyze L-Hcy-thiolactone (but not D-Hcy-thiolactone) to Hcy in vitro, but whether this reflects a physiological function has been unknown. Here, we show that Blmh (-/-) mice excreted in urine 1.8-fold more Hcy-thiolactone than wild-type Blmh (+/+) animals (P = 0.02). Hcy-thiolactone was elevated 2.3-fold in brains (P = 0.004) and 2.0-fold in kidneys (P = 0.047) of Blmh (-/-) mice relative to Blmh (+/+) animals. Plasma N-Hcy-protein was elevated in Blmh (-/-) mice fed a normal (2.3-fold, P < 0.001) or hyperhomocysteinemic diet (1.5-fold, P < 0.001), compared with Blmh (+/+) animals. More intraperitoneally injected L-Hcy-thiolactone was recovered in plasma in Blmh (-/-) mice than in wild-type Blmh (+/+) animals (83.1 vs. 39.3 μM, P < 0.0001). In Blmh (+/+) mice injected intraperitoneally with D-Hcy-thiolactone, D,L-Hcy-thiolactone, or L-Hcy-thiolactone, 88, 47, or 6.3%, respectively, of the injected dose was recovered in plasma. The incidence of seizures induced by L-Hcy-thiolactone injections (3,700 nmol/g body weight) was higher in Blmh (-/-) than in Blmh (+/+) mice (93.8 vs. 29.5%, P < 0.001). Using the Blmh null mice, we provide the first direct evidence that a specific Hcy metabolite, Hcy-thiolactone, rather than Hcy itself, is neurotoxic in vivo. Taken together, our findings indicate that Blmh protects mice against L-Hcy-thiolactone toxicity by metabolizing it to Hcy and suggest a mechanism by which Blmh might protect against neurodegeneration associated with hyperhomocysteinemia and Alzheimer's disease.     

Antioxidant gene expression in active and sedentary house mice (Mus domesticus) selected for high voluntary wheel-running behavior

We present liver mRNA levels of the two antioxidant enzymes catalase (CAT) and Mn-superoxide dismutase (SOD2) in four treatment groups of house mice assayed by RNase protection at 20 months of age. These groups were mice from four replicate selection and four replicate control lines from the sixteenth generation of selective breeding for high voluntary wheel running, housed with or without running wheels from age 3 weeks through 20 months. Exercising control females had induced CAT expression; SOD2 exhibited a similar pattern in females from two of the four control lines. Exercising male mice had induced CAT expression, but not SOD2 expression, irrespective of genetic background. We discuss these results with respect to both evolutionary (genetic) and training (exercise-induced) adaptations and explore predictions of these results in relation to the oxidative-damage theory of senescence.     

Plasmodium berghei: relationship between protective immunity and anti-sporozoite (CSP) antibody in mice

Protective immunity and production of anti-sporozoite (CSP) antibody was studied in A/J mice injected with X-irradiated sporozoites using different immunization schedules and antigen doses. Data were also obtained on the immunogenicity of X-irradiated as compared to nonirradiated sporozoites. After a single immunization (1.5 × 10⁵ or 7.5 × 10⁴ X-irradiated sporozoites) a number of animals was completely protected when challenged, but the percentage of protected mice varied considerably from experiment to experiment. Maximal protection was obtained 7 days after the immunization. When the first injection of parasites was followed by a single booster administered 3, 4 or 5 days later, protection was considerably enhanced and the results more consistent. After a single injection of 1.5 × 10⁵ or 7.5 × 10⁴ sporozoites, CSP antibody was detectable from the 19th and 23rd day, respectively, i.e., at a time point when protection was diminishing. This antibody persisted only for a short period. When a single booster was given soon after the first injection, CSP antibody was present in the sera of all the mice from the ninth day on and persisted for greater than 80 days. A single dose of X-irradiated sporozoites injected into rats, induced antibody (CSP) formation which reached a peak after 2 weeks and persisted at this level for more than 3 months. However in rats injected with viable sporozoites, the antibody titers fell rapidly and became undetectable after 4 weeks.From these data we can conclude that (a) the immune response induced by attenuated X-irradiated sporozoites is considerably longer-lasting than that induced by viable sporozoites; (b) CSP antibodies are not detectable during the early stages of the immune response; and (c) protective immunity precedes the presence of detectable serum and antibodies.     

Signaling pathway factors expression in renal tissue of apoE-knockout mice

Abstract

Apolipoprotein E (apoE) is regarded as one of the major plasma lipoproteins, and it plays an important role in the transport and metabolism of lipids. apoE can be found in multiple tissues, such as liver, kidney, jejunum, urinary bladder, ileum, colon, brain, adrenal glands, lung, ovary, spleen, pancreas, and testis, etc. As a secreted protein, it plays an important role in the systemic lipoprotein metabolism and vascular wall homeostasis and in the pathogenesis of renal diseases. apoE-knockout (apoE(?/?)) mice is a classic model of atherosclerosis and renal diseases. However, no review summed up the signaling pathway factors expression in renal tissue of apoE-knockout mice. The literatures were searched extensively and this review was performed to review the signaling pathway factors expression in renal tissue of apoE-knockout mice.     

Prognostic prediction and diagnostic role of intercellular adhesion molecule-1 (ICAM1) expression in clear cell renal cell carcinoma

The intercellular adhesion molecule-1 (ICAM1) has been reported to function in multiple malignancies, but its effect on clear cell renal cell carcinoma (ccRCC) hasn’t been discussed yet. This study aimed to identify the potential role of ICAM1 in prognostic prediction and early diagnosis of ccRCC. ICAM1 expression was inspected by immunohistochemistry and correlated with clinicopathologic variables. Association between protein expression and cancer-specific survival (CSS) of ccRCC patients was evaluated and the value of area under the receiver operating characteristics (ROC) curve (AUC) was calculated to measure the protein’s diagnostic accuracy. ICAM1 was positively immunostained in 83.2 % of 173 ccRCC tissues, but negatively immunostained in all the para-cancerous normal epitheliums of renal tubules. High ICAM1 expression was significantly related to male sex (P = 0.00241), T3/T4 stage (P = 0.02249), non-N0M0 stage (P = 0.03797) and positive renal pelvis invasion (P = 0.04227). Kaplan–Meier survival analysis illustrated that high ICAM1 expression was significantly correlated to a decreased CSS (P = 0.00006). Multivariate Cox analysis indicated that ICAM1 was an independent predictor for CSS of patients (P = 0.00451). Furthermore, the AUC value of ICAM1 in diagnosing ccRCC was 0.916 (P < 0.00001). In conclusion, high ICAM1 expression on tumor cells indicates a poor outcome of patients and ICAM1 is likely to be an independent predictor for the prognosis of ccRCC. Moreover, ICAM1 has a high AUC value and may be a potential and useful diagnostic marker.     

The protective role of thiola and soybean seeds against the genotoxicity induced by potassium dichromate in mice

Available data suggesting the occurrence of "bystander effects" (i.e. damage induction in cells not traversed by radiation) were collected and critically evaluated, in view of the development of low-dose risk models. Although the underlying mechanisms are largely unknown, cellular communication seems to play a key role. In this context, the main features of cellular communication were summarised and a few representative studies on bystander effects were reported and discussed. Three main approaches were identified: (1) conventional irradiation of cell cultures with very low doses of light ions; (2) irradiation of single cells with microbeam probes; (3) treatment with irradiated conditioned medium (ICM), i.e. feeding of unexposed cells with medium taken from irradiated cultures. Indication of different types of bystander damage (e.g. cell killing, gene mutations and modifications in gene expression) has been found in each of the three cases. The interpretations proposed by the investigators were discussed and possible biases introduced by specific experimental conditions were outlined. New arguments and experiments were suggested, with the main purpose of obtaining quantitative information to be included in models of low-dose radiation action. Implications in interpreting low-dose data and modelling low-dose effects at cellular and supra-cellular level, including cancer induction, were analysed. Possible synergism with other low-dose specific phenomena such as adaptive response (AR) (i.e. low-dose induced resistance to subsequent irradiation) was discussed.     

Decoy receptor 3 inhibits renal mononuclear leukocyte infiltration and apoptosis and prevents progression of IgA nephropathy in mice

The progression of IgA nephropathy (IgAN), the most frequent type of primary glomerulonephritis, is associated with high levels of mononuclear leukocyte infiltration into the kidney. These cells consist mainly of T cells and macrophages. Our previous study showed that a decoy receptor 3 (DCR3) gene therapy can prevent the development of a mouse autoimmune glomerulonephritis model by its potent immune modulating effects (Ka SM, Sytwu HK, Chang DM, Hsieh SL, Tsai PY, Chen A. J Am Soc Nephrol 18: 2473-2485, 2007). Here, we tested the hypothesis that DCR3 might prevent the progression of IgAN, an immune complex-mediated primary glomerulonephritis, by inhibiting T cell activation, renal T cell/macrophage infiltration, and protecting the kidney from apoptosis. We used a progressive IgAN (Prg-IgAN) model in B cell-deficient mice, because the mice are characterized by a dramatic proliferation of activated T cells systemically and progressive NF-κB activation in the kidney. We treated the animals with short-term gene therapy with DCR3 plasmids by hydrodynamics-based gene delivery. When the mice were euthanized on day 21, we found that, compared with empty vector-treated (disease control) Prg-IgAN mice, DCR3 gene therapy resulted in 1) systemic inhibition of T cell activation and proliferation; 2) lower serum levels of proinflammatory cytokines; 3) improved proteinuria, renal function, and renal pathology (inhibiting the development of marked glomerular proliferation, crescent formation, glomerulosclerosis, and interstitial inflammation); 5) suppression of T cell and macrophage infiltration into the periglomerular interstitium of the kidney; and 5) a reduction in apoptotic figures in the kidney. On the basis of these findings, DCR3 might be useful therapeutically in preventing the progression of IgAN.     

Karyomegaly and intranuclear inclusions in the renal tubules of sentinel ICR mice (mus musculus)

Among 585 sentinel ICR mice (Mus musculus), 8 (7 female, 1 male) had unusual microscopic lesions in the kidney. Light microscopy revealed occasional tubular epithelial cells with large, karyomegalic nuclei that contained intranuclear inclusions and marginated chromatin. These cells were randomly present in the cortex and medulla but were more prominent near the corticomedullary junc tion. Rare pyknotic cells and mild interstitial infiltrates of lymphocytes and plasma cells were associated with occasional foci of abnormal cells. Electron microscopy performed on 2 (1 female, 1 male) of the mice demonstrated intranuclear inclusions composed of abundant flocculent, electron-lucent material. No viral particles or other pathogens were identified. General health monitoring that included serology, microbiology, parasitology, necropsy, and histopathology was negative for pathogens. Polymerase chain reaction-based testing for polyomavirus and immunohistochemistry for adenovirus were performed on 5 of the 7 female mice; all were negative for both viruses. In light of microscopy findings and the lack of evidence for an infectious agent, the tubular lesions were considered degenerative changes, possibly due to a toxic insult. The cause and significance of the findings in these mice can not be explained fully.