Incomplete protection mechanism against vesico-ureteral reflux and hydronephrosis in the inbred mouse strain DDD

We have previously reported the occurrence and inheritance mode of hydronephrosis in the inbred mouse strain DDD. The present investigation examined the possibility that hydronephrosis may be caused by a vesico-ureteral reflux (VUR). Bladder pressure was measured under anaesthesia in 3 strains of mice (DDD, ddY and C57BL/6). VUR was demonstrated by lower bladder pressure only in the DDD strain. Loading pressure into the renal pelvis (LPP) was significantly higher in DDD than in C57BL/6 (P less than 0.001). Correlations between LPP and severity of hydronephrosis were significantly positive in DDD and ddY, indicating that mice showing higher LPPs had the severest disease. Scanning electron micrography revealed that the ureteral orifice of DDD (100-300 microns) was much larger than in C57BL/6 (30 microns), and thus offered scant protection against VUR in DDD. These results suggest that DDD hydronephrosis caused by VUR is related primarily to the absence of an adequate protection mechanism in the ureteral orifice.     

Inheritance of hydronephrosis in the inbred mouse strain DDD

The mode of inheritance of hydronephrosis was investigated by crossing inbred DDD mice having a high incidence of hydronephrosis and C57BL/6 mice having normal kidneys. In the males, incidences of hydronephrosis in F1 animals were intermediate between the two parental strains at a rate of 32.6% in (DDD x C57BL/6)F1 and 23.4% in reciprocal F1. The same tendency was observed in F2 male animals. In BCF1 males, the number of affected mice was higher in (C57BL/6 x DDD) F1 x DDD (72.4%) than in (DDD x C57BL/6)F1 x C57BL/6 (11.1%). A few affected mice were found among the females of hybrids F1, F2 and BCF1. These results suggested that hydronephrosis in the DDD strain of mice was controlled by polygenes, and that male hormones may have some effect on the occurrence of hydronephrosis.     

Influence of testosterone on hydronephrosis in the inbred mouse strain DDD

Hereditary hydronephrosis was detected in all of the male mice of DDD inbred strain maintained at the National Institute of Animal Health Japan, but in only a few of the females. From the standpoint that male hormones are related to the development of hydronephrosis in this strain, the incidence and severity of the disease were investigated in gonadectomized mice treated with testosterone. In the males, the incidence of hydronephrosis was 50% (7/14) in the control (gonadectomized) group, and 73.3% (11/15), 100% (13/13) and 100% (12/12) in the 0.1 mg, 3.3 mg and 10 mg treatment groups respectively. The same tendency was observed in the female animals, though the incidence in each group was not so high. In both sexes the degree of severity increased in proportion to the dose of testosterone administrated. Blood testosterone levels were higher in intact DDD mice than in C57BL/6 mice, which had normal kidneys in both sexes. These results suggest that male hormones play a significant role in the development of hydronephrosis.     

Incidence of hydronephrosis among several production colonies of outbred Sprague-Dawley rats

The incidence of hydronephrosis was determined in nine production colonies of Crl:CD (SD) BR rats (CD rats). Kidneys from 3909 rats were examined and 79 (2.0%) had unilateral or bilateral hydronephrosis. A colony with a relatively high incidence of hydronephrosis (4.1%) was chosen for further study. In unselected rats from this colony the incidence in females (87/1882, 4.6%) was not significantly different from that in males (79/1862, 4.2%). In the same group of rats, hydronephrosis was observed most frequently in the right kidney only (2.3%), followed by bilateral involvement (1.2%) and the left kidney only (0.8%). By selection and inbreeding, the incidence of hydronephrosis was increased dramatically (to 33.6%) in two generations. Hydronephrosis in the CD rat appears to be a highly heritable trait, most likely involving more than one gene.     

VURD syndrome managed by pyelostomy

We report a case of VURD syndrome in a three day old neonate who was diagnosed with hydronephrosis on a prenatal ultrasound. Severe tortuosity and dilation of the upper urinary tracts in the presence of progression of hydronephrosis or a persistently elevated creatinine may favor a proximal urinary diversion rather than primary valve ablation or cutaneous vesicostomy. Because of a persistently elevated serum creatinine, a nonfunctioning kidney with grade 4/5 vesicoureteral reflux and worsening contralateral hydronephrosis despite lower tract drainage, a left cutaneous pyelostomy was performed, contralateral to the kidney involved with VURD. Postoperatively the serum creatinine stabilized at 1.0 mg/dl and decreased to 0.3 mg/dl at one month of age.     

Characterization of dominant hereditary cataract in DDD/1 mice

We found a female cataractous DDD/1-nu/+ mouse and established a hairy mutant strain (DDD/1-Cti/Cti) with 100% incidence of cataract from it by repeating sibmating. Genetic studies demonstrated that a single autosomal semidominant gene controls cataractogenesis. This gene was named Cti. In homozygotes, DDD/1-Cti/Cti, the lenses began to opacify at 14 days of fetal life and were recognized clinically as cataract at 13-14 days of age when the eyes first open. The opacification became more and more intense with age and looked like mature cataract at 28-42 days of age. However, clarification of the opacified lenses commenced at the periphery after 56 days of age and expanded to the inside with time, and only an opaque spot was left at the center at 140 days of age. In heterozygotes, DDD/1-Cti/+, the lenses were recognizable as cataract after 28 days and became like mature cataract around 35 days of age. The opacity began to be lightened at 42 days and the lenses appeared normal at 56 days of age. Both lenses and eyeballs developed in similar courses in DDD/1(-)+/+, -Cti/+ and -Cti/Cti, although slightly retarded in the last. Microphthalmia was not accompanied even in DDD/1-Cti/Cti. The lens water content remained higher during the time when intense lens opacity continued in DDD/1-Cti/Cti and -Cti/+. Background genes appeared to affect the expression of Cti. DDD/1-Cti(-)+ mice may provide a model for researches into clarification of opaque lenses. A discussion concerning the possible allelism of Cti and Cts with Lop was made based on their phenotypic characteristics.     

Strain difference in mouse natural killer activity augmented by mouse interferon and poly I.C

The level of natural killer (NK) activity was found to vary considerably among several mouse strains. In vivo and in vitro, interferon (IFN) and IFN inducers have been shown to augment mouse NK activity. C3H/He mice showed high NK activity, DDD/1 and A/J mice low NK activity, and C57BL/6, BALB/c and DBA/2 mice intermediate NK activity after injection with polyinosinic polycytidylic acid (poly I. C.). The same NK activity correlation was observed in nontreated mice, but the NK activities were lower compared with the poly I. C.-injected mice. Moreover, the DDD/1 and A/J mice showed almost no augmentation of NK activity on injection with poly I.C. In vivo, C3H/He, BALB/c and C57BL/6 mice injected with IFN showed augmented NK activity, but DDD/1 mice showed no such reaction. In vitro, C3H/He, BALB/c and C57BL/6 mouse spleen cells treated with IFN also showed augmented NK activity, but DDD/1 mouse spleen cells showed almost none. F1 hybrids between high (C3H/He) and low (DDD/1) NK-activity strains showed high NK activity. Thus, activity is dominant over low activity. The segregation of (DDD/1 X C3H/He) Fl X DDD/1 back-cross mice suggested that the strain differences in NK activity are under polygenic control.     

Hereditary hydronephrosis in C57BL/KsJ mice.

We sought to determine if the incidence of renal hydronephrosis in male C57BL/KsJ mice increased with age and if grossly normal kidneys would develop hydronephrosis over time. Spontaneous hydronephrosis was found incidentally in 32% of 234 male C57BL/KsJ mice killed as pancreas donors for islet transplantation experiments. The incidence of hydronephrosis increased with age; the incidence was 15% in 6- to 8-week-old mice, 52% in 8- to 10-week-old mice and 63% in 11- to 15-week-old mice (P less than 0.001). Additional mice received islet isografts beneath the renal capsule. Only mice with grossly normal kidneys received islet grafts. These same kidneys were then re-examined when the graft recipients were killed at the end of the experiment and the incidence of hydronephrosis was determined. The conversion of normal kidneys to hydronephrotic kidneys increased with the time since islet transplantation. Kidneys re-examined less than 4 weeks since transplantation had only 5.8% new hydronephrosis, while those re-examined later than 4 weeks after transplantation had a new hydronephrosis incidence rate of 40% (P less than 0.001). Our findings suggest that hydronephrosis is hereditary but not congenital, that it develops rapidly, and that it can complicate experiments using this strain. This may also represent a useful new animal model of progressive hydronephrosis.     

Distinct responses of a recA::luxCDABE Escherichia coli strain to direct and indirect DNA damaging agents.

The recombinant Escherichia coli strain DPD2794 containing a recA::luxCDABE fusion is used to detect genotoxicity of various chemicals. Genotoxic agents were previously categorized into two groups, Direct DNA Damaging (DDD) agents and Indirect DNA Damaging (IDD) agents; these two groups have been distinguished with this strain. Minimum detectable concentrations of the DDD agents were about one to five orders of magnitude lower than those of the IDD agents. The response patterns of this strain to DDD agents differed from those to IDD agents in terms of kinetics and the forms of the dose-dependent response.     

Studies of experimental allergic encephalomyelitis by using encephalitogenic T cell lines and clones in euthymic and athymic mice

The role of T-T cell interactions in the clinical course of acute experimental allergic encephalomyelitis (EAE) in mice was investigated. Myelin basic protein (MBP)-reactive and encephalitogenic T cell clones were established from long-term lines derived from susceptible strain SJL/J mice and resistant strain DDD/1 mice. The lines and clones from DDD/1 mice were obtained by immunization of congenitally athymic mice of DDD/1 origin, which had been reconstituted with syngeneic Lyt-2+-depleted splenic T cells. The clones derived from both strains bore surface phenotypes of Lyt-1+, 2- and L3T4+, and proliferated well in response to rat, rabbit, bovine, and guinea pig MBP in the presence of antigen-presenting cells with I-As. Passive EAE could be induced in syngeneic normal recipients by these clones as well as by the lines from which the clones were derived. The clinical features of the clone-induced EAE were essentially the same as those of the line-induced EAE. Furthermore, DDD/1 athymic recipients developed signs of acute EAE by the adoptive transfer of I-A-compatible syngeneic and allogeneic T cell clones, in which there was no significant difference in time of onset, maximum severity, or prognosis. These results indicate that the entire clinical course of acute EAE can be elicited by a single population of MBP-reactive T cells in the absence of the thymus and other populations of primed or unprimed T cells.     

Characterization of N-type and dually permissive cells segregated from mouse fibroblasts whose Fv-1 phenotype could be modified by another independently segregating gene(s).

Though the inbred DDD mouse strain is essentially of the N type, the primary culture of this strain was about 100-fold more sensitive to B-tropic WN1802B virus than were the typical N-type strains (C3H/He, C57L, etc.). After cloning, DDD mouse cells segregated two types of cells, typical N-type cells and cells lacking in Fv-1 restriction. As both types of cells so far tested retained glucose-6-phosphatase-1 coded by a locus closely linked to Fv-1 and genetic cross experiments indicated the presence of a gene(s) modifying the Fv-1 phenotype, variation in Fv-1 restriction could presumably be brought about by genetic changes in a gene(s) other than Fv-1 itself. N-type and dually permissive cell clones were similarly established from the inbred G mouse. Compositions of polypeptides labeled with [35S]methionine in the N-type and dually permissive cells of DDD and G mouse origins were compared by two-dimensional gel electrophoresis. The polypeptide maps of these cells were similar except for a few spots. Among these dissimilar spots, a spot of about 20,000 daltons with a pI of about 5.5 was always present in N-type cells, whereas it was absent in dually permissive cells. In DDD mouse-derived clones, a proportional relation was observed between the intensity of the spot and the restriction to the B-tropic virus.     

Strain Differences in the Immunogenicity of Aggregated Human IgG and the Adjuvant Action of Lipopolysaccharide on the Low-Responder Strain of Mice

Strain differences in the antibody response to human IgG (HGG) were observed when aggregated HGG was injected intravenously. Lipopolysaccharide (LPS) administered subsequently markedly enhanced the antibody response to HGG in low responder C57BL/6 mice as compared with that in high responder DDD, C3H/He or (C57BL/6 × DDD)F₁ mice. Aggregate-free preparation of HGG at a dose of 0.5 mg induced immunological tolerance in all strains of mice tested. LPS injected subsequently converted tolerogenic, aggregate-free HGG into immunogen in DDD mice but not in C57BL/6 mice. To determine the correlation between adjuvanticity and mitogenicity of LPS, spleen cells from normal mice were cultured in the presence of LPS and ³H-thymidine uptake was measured. Spleen cells of DDD mice incorporated three times as much ³H-thymidine as those of C57BL/6 mice. There seems no strong correlation between both activities of LPS. The data obtained are discussed in terms of strain differences in the macrophage function for processing the antigen.     

Strain differences in response of Sprague-Dawley and Long Evans Hooded rats to the teratogen nitrofen

Administration of nitrofen (2,4-dichloro-4'-nitrodiphenyl ether) during organogenesis in rodents produces neonatal lethality accompanied by lung hypoplasia, diaphragmatic hernias, heart anomalies, and hydronephrosis. Different strains of rats, Long Evans Hooded (LEH) and Sprague-Dawley (SD), are reported to have different malformation responses to prenatal exposure, which could be due to true strain differences, to different levels and times of exposure, or to the use of different methods for detecting visceral malformations. In the present study, LEH, SD, and "virus-antibody-negative" SD (VAN-SD) rats were identically exposed to 0, 6.25, 12.5, or 25 mg/kg/day of nitrofen by gavage in corn oil on days 6 15 of gestation. At term, half of the litter was examined by the Wilson method of razorblade sectioning and the remainder by a modified Staples method of fresh visceral examination. The two methods were equally sensitive for detecting diaphragm, kidney, and lung anomalies, whereas heart malformations were more frequently identified with fresh visceral examination. The frequency of total malformations did not vary across strains at any dose, but there were substantial differences in the pattern of malformations in each strain. SD and VAN-SD rats responded similarly for all malformations, but had significantly higher incidences of diaphragm and lung anomalies than LEH rats. Conversely, LEH rats had significantly elevated levels of kidney anomalies compared to SD and VAN-SD rats, whereas frequency of heart malformations was low and comparable across strains. These results suggest that true strain differences exist in the pattern of malformation produced by prenatal exposure to nitrofen that may be based on genetic differences in embryonic susceptibility.     

NON-HISTONE CHROMOSOMAL PROTEINS IN MOUSE BRAIN AT DIFFERENT STAGES OF DEVELOPMENT AND IN A TRANSPLANTABLE MOUSE TERATOMA

Abstract— Non-histone chromosomal proteins (NHCP) from mouse brain at different stages of development and from adult liver and kidney of strain related mice were analyzed by SDS-polyacrylamide gel electrophoresis and were compared with the mouse teratoma, OTT-6050. The fetal, neonatal and adult brains were qualitatively similar in their NHCP profiles but had quantitative differences. The NHCP composition of the adult brain was clearly distinct from that of the liver and kidney and was dissimilar from that of the teratoma.     

Inheritance of susceptibility to the myeloproliferative sarcoma virus: effect of the Fv-2 locus and evidence for a myeloproliferative sarcoma virus resistance locus.

Myeloproliferative sarcoma virus (MPSV) causes a generalized stem cell leukemia with erythroid and myeloid hyperplasia in adult mice. MPSV also transforms fibroblasts. Mice congenic for the Fv-2 locus showed marked differences in susceptibility to MPSV according to the Fv-2 genotype. MPSV was injected into C57BL/6 Fvs and C57BL/6 Fv-2r mice congenic except for the Fv-2 locus. C57BL/6 mice with the Fvs genotype were much more susceptible to MPSV than were those with the Fvr genotype. Both DDD Fv-2r mice congenic with DDD Fv-2s mice except for the Fv-2 locus and DDD Fv-2s mice, however, were sensitive to spleen focus formation by MPSV. These data indicate that at least one additional resistance locus to MPSV is present in C57BL/6 mice but not in DDD mice. Both the Fv-2 locus and the putative MSPV resistance locus (loci) Mpsvr appear to be epistatic to either of the sensitivity loci. Fibroblast focus formation by MPSV was obtained well in C57BL/6 Fv-2r and C57BL/6 Fvs fibroblasts, indicating that the genes for MPSV resistance (Fv-2r and Mpsvr) were not operating in fibroblast cells. A model is proposed which may account for the differences in response of genetically different mice to MPSV and Friend spleen focus-forming virus.     

"The beneficial and protective effects of hydronephrosis"

Hydronephrosis is generally considered a pathologic process, and especially in infancy is widely viewed as caused by obstruction, potentially injurious to the kidney and in need of expeditious surgical treatment. However a number of clinical and experimental studies suggest exactly the opposite: that hydronephrosis is not pathological but actually a compensating mechanism designed to protect the kidney from high pressures and renal damage. Furthermore, because hydronephrosis in the infant involves an already compliant and distensible renal pelvis it appears to be uniquely beneficial. Herein the experimental basis for a counterargument challenging the harmful effects of hydronephrosis will be presented.     

Obstructive Uropathy Secondary to Uterine Leiomyoma in a Chimpanzee (Pan troglodytes)

Complications due to uterine leiomyomata in chimpanzees have rarely been documented. Here we describe a female chimpanzee that developed severe hydronephrosis in the right kidney due to leiomyoma. Because hysterectomy did not alleviate the hydronephrosis, nephrectomy was elected. After these procedures, the chimpanzee is doing well. Leiomyomata screening programs with treatment algorithms are a useful component of a comprehensive chimpanzee program.The prevalence rates for the occurrence of uterine leiomyomata, or fibroids, in female captive chimpanzees are reported to be similar to those for humans.¹⁶ However, in contrast to humans, complications secondary to uterine leiomyomata in chimpanzees have been documented infrequently. Here we present a case of obstructive uropathy due to uterine leiomyoma that resulted in severe hydronephrosis and surgical removal of a kidney in a female chimpanzee.     

Comparison of background factors relevant to mammary tumorigenesis between DDD/1-Mtv-2/Mtv-2 congenic and DDD/1 mice

To elucidate the possible participation of the Mtv-2 gene in the background factors relevant to mammary tumorigenesis, DDD/1-Miv-2/Mtv-2 (DDD-Mtv-2) congenic and DDD/1 background mice were compared for endocrine and immune organs, mammary gland development, expression of mouse mammary tumor virus (MMTV)-gp 52 antigen, hyperplastic alveolar nodules (HAN) and mammary tumor incidence. The congenic strain had been established by introducing Mtv-2 from GRS/AJms (GR) into DDD/1 mice by repeated 12 backcrosses. Body, thymus, spleen, uterus, ovary, adrenal and pituitary weights, histology of the ovary and mammary gland development showed no differences ascribable to Mtv-2 between both strains of mice at 4,6 and 12 months of age. In contrast, MMTV-gp 52 antigen expression, HAN and mammary tumor occurred in DDD-Mtv-2 but not in DDD/1 mice. These results showed that the Mtv-2 gene stimulates mammary tumorigenesis by constitutional production of endogenous MMTV which transforms mammary epithelial cells but not by influencing the background factors relevant to mammary tumorigenesis. Furthermore, the expression of Mtv-2 appeared to be lower on the DDD/1 than on the GR background.