RESUMEN
BACKGROUND: Toll-like receptor (Tlr) 9 is capable of recognizing exogenous and/or endogenous nucleic acids and plays a crucial role in innate and adaptive immunity. Recently, we showed that Tlr9 is overexpressed in podocytes, a component of the blood-urine barrier (BUB), in glomeruli of autoimmune glomerulonephritis (AGN) model mice. This study investigated the activation of peritubular capillary (PTC) endothelial cells (ECs), a component of the BUB in the tubulointerstitium, through overexpressing Tlr9, and the subsequent development of tubulointerstitial lesions (TILs) in AGN model mice. METHODS: Lupus-prone BXSB/MpJ-Yaa (Yaa) and BXSB/MpJ (BXSB) mice were used as an AGN model and control, respectively. In addition to histopathological and ultrastructural techniques, protein and mRNA levels were also evaluated. The relationship between Tlr9 and TIL indices was analyzed by statistical correlation analysis. RESULTS: Yaa mice developed TILs and showed strong Tlr9 mRNA expression in PTC ECs at 24 weeks (wks) of age. However, BXSB mice showed no TIL but faint expression of Tlr9 mRNA at 8 and 24 wks of age. Tlr9 protein localization on PTC was almost absent in BXSB mice at both ages but intense expression was found in Yaa mice only at 24 wks of age. Relative mRNA expression of Tlr9 and its putative downstream cytokines, including interleukin 1 beta ( Il1b), Il6, interferon gamma ( Ifng), and tumor necrosis factor alpha ( Tnf) was markedly increased in isolated tubulointerstitium from Yaa mice at 24 wks of age. Furthermore, electron microscopy examination revealed PTC injury and TIL in Yaa mice at 24 wks. The expression level of Tlr9 in the tubulointerstitium was correlated with inflammatory cells in TILs, injured PTC, Ilb and Tnf expression, and damaged tubules ( P < 0.05 and 0.01). CONCLUSION: Induced expression of Tlr9 in ECs correlates with PTC injury and the development of TILs in lupus-prone AGN model mice.
Asunto(s)
Lupus Eritematoso Sistémico/genética , Nefritis Intersticial/genética , Receptor Toll-Like 9 , Animales , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Expresión Génica , Humanos , Glomérulos Renales/patología , Lupus Eritematoso Sistémico/patología , Ratones , Nefritis Intersticial/patología , ARN Mensajero , Reacción en Cadena en Tiempo Real de la Polimerasa , Estadísticas no ParamétricasRESUMEN
Ovulation and oocyte-pick-up are essential processes in fertilization. Herein, we found associations between autoimmune disease and the aforementioned processes in mice. At three and six months, along with the evaluation of autoimmune disease indices, the ovary, mesosalpinx, and oviducts were histologically examined in C57BL/6, MRL/MpJ, and MRL/MpJ-Fas lpr/lpr mice as healthy control, mild and severe models of autoimmune disease, respectively. In superovulated mice, the number of "oocyte cumulus complexes" found in the ampulla was macroscopically counted, and that of "ovulated oocytes" was histologically evaluated, as indicated by ruptured follicles or corpora hemorrhagica in ovaries. Finally, the oocyte-pick-up rate was calculated. In MRL/MpJ-Fas lpr/lpr mice, the oocyte-pick-up rate decreased with disease-related deterioration, unlike in other mouse strains. Further, more ovulated oocytes were found in MRL/MpJ mice than in C57BL/6 mice, and this number significantly decreased with aging in MRL/MpJ-Fas lpr/lpr mice. Numerous T-cells infiltrated into the infundibulum or a part of the mesosalpinx in aged MRL/MpJ-Fas lpr/lpr mice, and their infundibulum showed swelling and fewer ciliated epithelial cells compared to that of C57BL/6 mice. In conclusion, the progression of severe autoimmune disease affected the oocyte-pick-up process through histopathological changes in the infundibulum. These results provide important insights into female infertility associated with autoimmune disease.
Asunto(s)
Enfermedades Autoinmunes/fisiopatología , Infertilidad Femenina/etiología , Oviductos/ultraestructura , Ovulación , Animales , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/patología , Modelos Animales de Enfermedad , Femenino , Ratones Endogámicos C57BLRESUMEN
The autoimmune-prone BXSB/MpJ-Yaa mouse is a model of membranous proliferative glomerulonephritis (MPGN). Severe MPGN has been reported only in male BXSB/MpJ-Yaa mice because of the Y-linked autoimmune accelerator (Yaa) locus. However, we show that female BXSB/MpJ mice develop age-related MPGN without Yaa. Female BXSB/MpJ mice clearly developed MPGN characterized by increased mesangial cells, thickening of the glomerular basement membrane (GBM), double contouring and spike formation of GBM with T-cell infiltrations and podocyte injuries corresponding with increased autoantibody production and albuminuria. Analysis of the renal levels of the Fc gamma receptor (Fcgr) and interferon-activated gene 200 (Ifi200) family genes, which are MPGN candidate genes localized to the telomeric region of chromosome 1 (Chr.1), showed that Fcgr2b levels decreased, whereas Fcgr3 and Ifi202b levels increased in female BXSB/MpJ mice compared with healthy C57BL/6 mice. Furthermore, in isolated glomeruli, microarray analysis revealed that Fcgr3, Fcgr4 and Ifi202b expression was higher in male BXSB/MpJ-Yaa mice than in male BXSB/MpJ mice. These findings indicate that the BXSB/MpJ-type genome causes age-related MPGN with significant contribution from the telomeric region of Chr.1, and Yaa enhances the expression of genes localizing to this locus, thereby leading to severe MPGN in male mice.
Asunto(s)
Enfermedades Autoinmunes/genética , Predisposición Genética a la Enfermedad , Glomerulonefritis/genética , Animales , Enfermedades Autoinmunes/inmunología , Cromosomas de los Mamíferos , Femenino , Expresión Génica , Glomerulonefritis/inmunología , Glomerulonefritis/patología , Glomerulonefritis/fisiopatología , Pruebas de Función Renal , Glomérulos Renales/inmunología , Glomérulos Renales/patología , Glomérulos Renales/ultraestructura , Masculino , Ratones , Ratones Endogámicos C57BL , Podocitos/metabolismo , Podocitos/patología , Telómero , Cromosoma YRESUMEN
We examined the role of Mag, an autoimmune susceptibility locus encoded by the telomeric region of MRL/MpJ mouse chromosome 1, in the pathogenesis of autoimmune exocrinopathy. At nine to 12 months of age, strain-specific differences were observed in the pancreas of the animals. B- and T-cell-containing periductal/perivascular cell infiltrations in the pancreases of MRL/MpJ and B6.MRLc1 congenic C57BL/6-background Mag-carrying strains were more severe than were those of C57BL/6. Pancreatic periductal/perivascular cell infiltration was observed frequently in A/J, AKR/N, B6.MRLc1, C57BL/6, and MRL/MpJ, moderately in DBA/1 and DBA/2, and rarely in BALB/c and C3H/He strains. Females tended to have greater pancreatic periductal/perivascular cell infiltration than males. C57BL/6 mice possessed defined borders between cell infiltrations and acini, but borders were indistinct in MRL/MpJ and B6.MRLc1 mice. We attributed this to the invasion of inflammatory cells between each acinus and the disruption of acinar cells around cell infiltrations in the latter strains. No strain-specific differences were observed in the appearance of fibrotic lesions and high endothelial venules in the cell infiltrates. The levels of serum anti-dsDNA antibodies and amylase, and mRNA expression of tumor necrosis factor-α and Fc gamma receptor III (encoded on Mag) in the pancreases, were elevated in MRL/MpJ- and B6.MRLc1-strain mice relative to C57BL/6. These results emphasized the crucial roles of Mag in the molecular and genetic pathogenesis of autoimmune-mediated pancreatitis.
Asunto(s)
Enfermedades Autoinmunes/genética , Cromosomas de los Mamíferos/genética , ADN/inmunología , Pancreatitis/genética , Animales , Enfermedades Autoinmunes/inmunología , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Masculino , Ratones , Ratones Endogámicos AKR , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Endogámicos MRL lpr , Pancreatitis/inmunología , ARN Mensajero/metabolismo , Receptores de IgG/genética , Factores Sexuales , Especificidad de la Especie , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
B6.MRLc1(82-100) congenic mice carrying the telomeric region of lupus-prone MRL chromosome 1 develop autoimmune glomerulonephritis (GN). The GN susceptibility locus of B6.MRLc1(82-100) contains the interferon activated gene 200 (Ifi200) family, which consists of Ifi202, 203, 204, and 205. Recently, Ifi202 was suggested as a candidate gene for murine lupus. In this study, we assessed the association between Ifi200 family and GN in several disease models. We compared the expression of Ifi200 family members in 24 organs between the C57BL/6 and B6.MRLc1(82-100). The expressions of Ifi200 family members differed between strains, and the most dramatic differences appeared in Ifi202 expression. Briefly, in the blood, immune organs, lungs, and testes mRNA expression was higher in B6.MRLc1(82-100) mice. In the kidney and immune organs, only Ifi202 expression increased with the development of GN in B6.MRLc1(82-100), and significant differences from C57BL/6 were observed even before disease onset. Ifi202 expression in the kidneys of BXSB, NZB/WF1, and MRL/lpr was also significantly high in the early- and late-disease stages. Furthermore, laser microdissection-reverse-transcriptase-polymerase chain reaction analysis confirmed the high Ifi202 expression in all areas of B6.MRLc1(82-100) kidneys. In conclusion, in the Ifi200 family, Ifi202 expressions in the kidney and immune organs significantly increased with GN progression.
Asunto(s)
Enfermedades Autoinmunes , Cromosomas de los Mamíferos , Regulación de la Expresión Génica , Glomerulonefritis , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones Endogámicos MRL lpr , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Glomerulonefritis/genética , Glomerulonefritis/inmunología , Glomerulonefritis/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Riñón/citología , Riñón/metabolismo , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Endogámicos NZB , Bazo/citología , Bazo/metabolismo , Timo/citología , Timo/metabolismo , Distribución TisularRESUMEN
Peroxisome proliferator-activated receptor (PPAR)-γ plays an important role in various cellular functions and its activation exerts protective effects in kidney diseases. In the present study, chronic kidney disease in cats was examined, and changes in renal expression of PPARγ were observed by use of immunohistochemistry. In normal kidneys, nuclei of the superficial cortical tubules, medullary tubules and glomerular cells expressed PPARγ. The vascular walls (tunica media) also showed positive expression. In diseased kidneys, the expression of PPARγ varied between the cases. Some cases showed strong expression, while others had weak expression. PPARγ expression in the nuclei of infiltrating mononuclear cells was also detected in over half of the cases. Although there was no significant relationship between the expression of renal PPARγ and the severity of kidney disease, the fact that there were many cases where the expression of renal PPARγ was reduced was an important finding, and might be one of the possible mechanisms underlying feline chronic kidney diseases.
Asunto(s)
Enfermedades de los Gatos/metabolismo , Enfermedades de los Gatos/patología , PPAR gamma/biosíntesis , Insuficiencia Renal Crónica/veterinaria , Animales , GatosRESUMEN
During the progression of chronic kidney disease (CKD), macrophage infiltration is a crucial event leading to tubulointerstitial fibrosis. In the present study, macrophages infiltrating renal tissue in dogs and cats with CKD were analysed immunohistochemically. Iba-1 was used as a pan-macrophage marker, CD204 was used as a marker of M2 macrophages and tumour necrosis factor (TNF)-α was used as a marker of M1 macrophages. Signals for Iba1 and CD204 were observed in the interstitium of all tested kidney samples. In dogs, the signals were diffusely scattered. In cats, both diffuse and focal signals were observed. Cells that were positive for Iba1 and CD204 were also observed in the tubular lumina in cats. Co-expression of Iba1 and CD204 was also observed in the infiltrating cells by immunofluorescence labelling, and these cells were negative for TNF-α. By quantitative analysis, the indices for Iba1- and CD204-positive cells were significantly correlated with the concentrations of plasma creatinine and/or urea and the extent of interstitial fibrosis in both dogs and cats. These results demonstrated that renal infiltration of M2 macrophages plays an important role in the progression of CKD in dogs and cats. The distribution pattern of the kidney-infiltrating macrophages was unique in cats and may be associated with a cat-specific renal fibrotic process.
Asunto(s)
Enfermedades de los Gatos/patología , Enfermedades de los Perros/patología , Macrófagos/patología , Insuficiencia Renal Crónica/veterinaria , Animales , Gatos , PerrosRESUMEN
INTRODUCTION: We evaluated the usefulness of xeno-Biosheets, an in-body tissue architecture-induced bovine collagenous sheet, as repair materials for abdominal wall defects in a beagle model. MATERIALS AND METHODS: Biosheets were prepared by embedding cylindrical molds into subcutaneous pouches of three Holstein cows for 2-3 months and stored in 70% ethanol. The Biosheets were 0.5 mm thick, cut into 2 cm × 2 cm, and implanted to replace defects of the same size in the abdominal wall of nine beagles. The abdominal wall and Biosheets were harvested and subjected to histological evaluation at 1, 3, and 5 months after implantation (n = 3 each). RESULTS: The Biosheet and bovine pericardiac patch (control) were not stressed during the suture operation and did not split, and patches were easily implanted on defective wounds. After implantation, the patch did not fall off and was not perforated, and healing was observed nacroscopically in all cases. During the first month of implantation, accumulation of inflammatory cells was observed along with decomposition around the Biosheet. Decomposition was almost complete after 3 months, and the Biosheet was replaced by autologous collagenous connective tissue without rejection. After 5 months, the abdominal wall muscle elongated from the periphery of the newly formed collagen layer and the peritoneum was formed on the peritoneal cavity surface. Regeneration of almost all layers of the abdominal wall was observed. However, almost all pericardium patches were remained even at 5 months with inflammation. CONCLUSION: Bovine Biosheets requiring no special post-treatment can be useful as off-the-shelf materials for abdominal wall repair.
Asunto(s)
Pared Abdominal/cirugía , Implantes Absorbibles , Bioprótesis , Hernia Ventral/cirugía , Herniorrafia/métodos , Implantación de Prótesis/métodos , Animales , Bovinos , Colágeno/administración & dosificación , Modelos Animales de Enfermedad , Perros , Regeneración Tisular Dirigida/métodos , Pericardio/trasplante , Prueba de Estudio Conceptual , Mallas Quirúrgicas , Andamios del Tejido , Trasplante HeterólogoRESUMEN
Renal capillary rarefaction is a crucial event that leads to tubulointerstitial damage during the progression of chronic kidney disease (CKD). In the present study, changes in CD34-positive renal capillaries were investigated in dogs and cats with CKD. A significant decrease in CD34-positive capillaries was observed in canine diseased kidneys, even at the early stage of disease. In cats, CD34-positive capillaries were well preserved in the diseased kidneys, with no link to the severity of CKD. Renal capillary rarefaction might be a trigger event that leads to the progression of CKD in dogs, rather than in cats.
Asunto(s)
Enfermedades de los Gatos/patología , Enfermedades de los Perros/patología , Insuficiencia Renal Crónica/veterinaria , Animales , Capilares/patología , Gatos , PerrosRESUMEN
Avian species have a unique renal structure and abundant blood flow into the kidneys. Although many birds die due to nephrotoxicity caused by chemicals, there are no early biomarkers for renal lesions. Uric acid level in blood, which is generally used as a renal biomarker, is altered when the kidney function is damaged by over 70%. Therefore, early biomarkers for kidney injury in birds are needed. In humans, glycomics has been at the forefront of biological and medical sciences, and glycans are used as biomarkers of diseases, such as carcinoma. In this study, a glycomics approach was used to screen for renal biomarkers in chicken. First, a chicken model of kidney damage was generated by injection of diclofenac or cisplatin, which cause acute interstitial nephritis (AIN) and acute tubular necrosis (ATN), respectively. The nephrotoxicity levels were determined by a blood chemical test and histopathological analysis. The plasma N-glycans were then analyzed to discover renal biomarkers in birds. Levels of 14 glycans increased between pre- and post administration in kidney-damaged chickens in the diclofenac group, and some of these glycans had the same presumptive composition as those in human renal carcinoma patients. Glycan levels did not change remarkably in the cisplatin group. It is possible that there are changes in glycan expression due to AIN, but they do not reflect ATN. Although further research is needed in other species of birds, glycans are potentially useful biomarkers for AIN in avian species.
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Pollos , Glicómica/métodos , Enfermedades Renales/veterinaria , Riñón/metabolismo , Enfermedades de las Aves de Corral/diagnóstico , Animales , Biomarcadores/análisis , Cisplatino , Diclofenaco , Enfermedades Renales/diagnóstico , MasculinoAsunto(s)
Glomerulonefritis Membranoproliferativa , Glomerulonefritis , Granulomatosis con Poliangitis , Anticuerpos Anticitoplasma de Neutrófilos , Glomerulonefritis/etiología , Granulomatosis con Poliangitis/complicaciones , Granulomatosis con Poliangitis/diagnóstico , Granulomatosis con Poliangitis/tratamiento farmacológico , HumanosRESUMEN
Inflammatory colorectal polyps (ICRPs) are characterized by the formation of multiple or solitary polyps with marked neutrophil infiltration in the colorectal area, and are speculated to be a novel form of breed-specific canine idiopathic inflammatory bowel disease (IBD). In human IBD, toll-like receptor (TLR) 2 and TLR4 have been reported to be involved in the pathogenesis of the disease. The aim of this study was to evaluate the expression of TLR2 and TLR4 mRNA in the colorectal mucosa of dogs with ICRPs by in-situ hybridization using an RNAscope assay. Samples of inflamed colorectal mucosa (n = 5) and non-inflamed mucosa (n = 5) from miniature dachshunds (MDs) with ICRPs and colonic mucosa from healthy beagles (n = 5) were examined. TLR2 and TLR4 hybridization signals were localized to the colorectal epithelium, inflammatory cells and fibroblasts in the inflamed colorectal mucosa of affected dogs. The signals were significantly greater in inflamed colorectal epithelium compared with non-inflamed epithelium of MDs with ICRPs and healthy beagles (P <0.05). These results suggest that increased expression of TLR2 and TLR4 mRNA in the inflamed colorectal mucosa results from not only inflammatory cell infiltration, but also the upregulation of TLR2 and TLR4 mRNA in the colonic epithelium.
Asunto(s)
Pólipos del Colon/veterinaria , Enfermedades de los Perros/metabolismo , Enfermedades Inflamatorias del Intestino/veterinaria , Receptor Toll-Like 2/biosíntesis , Receptor Toll-Like 4/biosíntesis , Animales , Perros , Procesamiento de Imagen Asistido por Computador , Hibridación in Situ , Mucosa Intestinal/metabolismo , ARN Mensajero , Recto , Receptor Toll-Like 2/análisis , Receptor Toll-Like 4/análisisAsunto(s)
Aminoacil-ARNt Sintetasas/inmunología , Autoanticuerpos/sangre , Creatina Quinasa/inmunología , Dermatomiositis/inmunología , Anciano , Especificidad de Anticuerpos , Dermatomiositis/sangre , Dermatomiositis/tratamiento farmacológico , Femenino , Humanos , Prednisolona/administración & dosificaciónRESUMEN
MRL/MpJ mice possess highly heat-shock-resistant spermatocytes (HRS) in comparison with C57BL/6 mice. This resistance depends on the MRL/MpJ-type loci at the 81 cM region of Chromosome (Chr) 1 and the 40 cM region of Chr 11. To evaluate the functions of these loci in detail, we examined the histopathological changes resulting from experimental cryptorchidism or transient scrotal heat stress (SHS) in the testes of C57BL/6-based congenic strains (B6.MRLc1, B6.MRLc11, and B6.MRLc1c11) carrying the MRL/MpJ-derived loci responsible for HRS. Among cryptorchid testes from congenic strains, those in B6.MRLc1c11 mice showed the highest heat resistance, indicating that the genetic interactions between MRL/MpJ-derived HRS loci on Chrs 1 and 11 may be important for maintaining spermatogenesis under continuous testicular hyperthermia. In contrast, immediately after SHS induction, germ cell loss via apoptosis was inhibited in B6.MRLc11 and B6.MRLc1c11 mice, similar to that in MRL/MpJ mice. However, this HRS phenotype was not observed in C57BL/6 or B6.MRLc1 mice after SHS induction. Furthermore, testicular calcification owing to long-term damage by SHS induction was inhibited in all congenic strains in comparison with that in C57BL/6 mice, indicating that each MRL/MpJ-derived locus on Chrs 1 and 11 acted independently to facilitate the recovery of heat-induced testicular damage by inhibiting calcification. B6.MRLc11 and B6.MRLc1c11 mice showed greater recovery in spermatogenesis than B6.MRLc1 mice 60 days after SHS induction. Therefore, the MRL/MpJ-derived HRS locus on Chr 11 might play an important role in recovery from heat stress damage. On the basis of these results, we concluded that MRL/MpJ-derived loci on Chrs 1 and 11 cooperatively or independently regulate testicular heat sensitivity depending on the various heat stresses.
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Calcinosis/patología , Respuesta al Choque Térmico/genética , Calor/efectos adversos , Espermatogénesis/genética , Testículo/patología , Animales , Apoptosis , Criptorquidismo/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Espermatocitos/citologíaAsunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo V/diagnóstico , Espondiloartropatías/etiología , Anciano , Diagnóstico Diferencial , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo V/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo V/fisiopatología , Antígeno HLA-B39/genética , Humanos , Músculo Esquelético/fisiopatología , Polimiositis , Tomografía Computarizada por Tomografía de Emisión de PositronesRESUMEN
Previously, the structure of the adult goat parotid salivary glands (PGs) was studied. However, little information was elucidated of the juvenile ones. This study aimed to clarify the correlations between the structure of goats' PGs and the nature of food intake among milk-suckling kids (MSKs) and diet-fed goats (DFGs). The secretory endpieces of the goats' PGs are of the pure serous type. The serous cells in MSKs showed apical accumulation of numerous secretory granules (SGs) of smaller size and of more intense positive periodic acid-Schiff reaction. Ultrastructurally, most of the SGs in the DFGs contained peripherally located inclusions that showed dense reaction products for acid phosphatase. In MSKs, the PGs showed less-developed basal infoldings, sparseness of the inter-cellular inter-digitations, fewer inter-cellular canaliculi and microvilli and also less-developed myoepithelial cells with fewer and shorter cytoplasmic processes. In conclusion, the less-developed membrane specializations and myoepithelial cells, as well as the accumulated SGs in the PGs of MSKs, suggest that it secretes less saliva with a little secretory activity than that of DFGs, which may be correlated with the reduced masticatory activity.