scholarly journals Genetic Background but Not Intestinal Microbiota After Co-Housing Determines Hyperoxaluria-Related Nephrocalcinosis in Common Inbred Mouse Strains

2021 ◽  
Vol 12 ◽  
Author(s):  
Qiuyue Ma ◽  
Melissa Grigorescu ◽  
Adrian Schreiber ◽  
Ralph Kettritz ◽  
Maja Lindenmeyer ◽  
...  
Keyword(s):  
Intestinal Microbiota ◽  
Genetic Background ◽  
Interstitial Fibrosis ◽  
Inbred Mouse ◽  
Intestinal Microbiome ◽  
Mouse Strains ◽  
Crystal Formation ◽  
Mrna Levels ◽  
Crystal Deposition ◽  
Caox Crystal

Calcium oxalate (CaOx) crystal formation, aggregation and growth is a common cause of kidney stone disease and nephrocalcinosis-related chronic kidney disease (CKD). Genetically modified mouse strains are frequently used as an experimental tool in this context but observed phenotypes may also relate to the genetic background or intestinal microbiota. We hypothesized that the genetic background or intestinal microbiota of mice determine CaOx crystal deposition and thus the outcome of nephrocalcinosis. Indeed, Casp1-/-, Cybb-/- or Casp1-/-/Cybb-/- knockout mice on a 129/C57BL/6J (B6J) background that were fed an oxalate-rich diet for 14 days did neither encounter intrarenal CaOx crystal deposits nor nephrocalcinosis-related CKD. To test our assumption, we fed C57BL/6N (B6N), 129, B6J and Balb/c mice an oxalate-rich diet for 14 days. Only B6N mice displayed CaOx crystal deposits and developed CKD associated with tubular injury, inflammation and interstitial fibrosis. Intrarenal mRNA expression profiling of 64 known nephrocalcinosis-related genes revealed that healthy B6N mice had lower mRNA levels of uromodulin (Umod) compared to the other three strains. Feeding an oxalate-rich diet caused an increase in uromodulin protein expression and CaOx crystal deposition in the kidney as well as in urinary uromodulin excretion in B6N mice but not 129, B6J and Balb/c mice. However, backcrossing 129 mice on a B6N background resulted in a gradual increase in CaOx crystal deposits from F2 to F7, of which all B6N/129 mice from the 7th generation developed CaOx-related nephropathy similar to B6N mice. Co-housing experiments tested for a putative role of the intestinal microbiota but B6N co-housed with 129 mice or B6N/129 (3rd and 6th generation) mice did not affect nephrocalcinosis. In summary, genetic background but not the intestinal microbiome account for strain-specific crystal formation and, the levels of uromodulin secretion may contribute to this phenomenon. Our results imply that only littermate controls of the identical genetic background strain are appropriate when performing knockout mouse studies in this context, while co-housing is optional.

scholarly journals Genetic background influences the impact of KLOTHO deficiency

2020 ◽  
Vol 52 (10) ◽  
pp. 512-516
Author(s):  
Jawad S. Salloum ◽  
Diane E. Garsetti ◽  
Melissa B. Rogers
Keyword(s):  
Genetic Background ◽  
Genetic Architecture ◽  
Disease Susceptibility ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Disease Models ◽  
Inbred Mouse Strains ◽  
Metabolic Interactions ◽  
Klotho Protein ◽  
The Impact

Genetic background is a key but sometimes overlooked factor that profoundly impacts disease susceptibility and presentation in both humans and disease models. Here we show that deficiency of KLOTHO protein, an important renal regulator of mineral homeostasis and a cofactor for FGF23, causes different phenotypes in 129S1/SvlmJ (129) and C57BL/6J (B6) mouse strains. The 129 strain is more severely affected, with decreased longevity, decreased body weight, and increased amounts of kidney calcification compared with B6 mice. Reciprocal F1 crosses of the strains also indicate a parentage effect on the Klotho phenotype with F1 KLOTHO-deficient progeny of B6 mothers and 129 fathers having more kidney calcification than progeny of 129 mothers and B6 fathers. Comparing and contrasting the genetic architecture leading to different phenotypes associated with specific inbred mouse strains may reveal previously unrecognized and important metabolic interactions affecting chronic kidney disease.

New tools for defining the 'genetic background' of inbred mouse strains

2007 ◽  
Vol 8 (7) ◽  
pp. 669-673 ◽  
Author(s):  
William M Ridgway ◽  
Barry Healy ◽  
Luc J Smink ◽  
Dan Rainbow ◽  
Linda S Wicker
Keyword(s):  
Genetic Background ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Inbred Mouse Strains

scholarly journals C57BL/6 and 129 inbred mouse strains differ in Gbp2 and Gbp2b expression in response to inflammatory stimuli in vivo

2019 ◽  
Vol 4 ◽  
pp. 124
Author(s):  
Barbara Clough ◽  
Ryan Finethy ◽  
Rabia T. Khan ◽  
Daniel Fisch ◽  
Sarah Jordan ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Genetic Background ◽  
Inbred Mouse ◽  
Shigella Flexneri ◽  
Protein Translation ◽  
Mouse Strains ◽  
Loss Of Function ◽  
Immune Priming ◽  
Mrna Induction

Background: Infections cause the production of inflammatory cytokines such as Interferon gamma (IFNγ). IFNγ in turn prompts the upregulation of a range of host defence proteins including members of the family of guanylate binding proteins (Gbps). In humans and mice alike, GBPs restrict the intracellular replication of invasive microbes and promote inflammation. To study the physiological functions of Gbp family members, the most commonly chosen in vivo models are mice harbouring loss-of-function mutations in either individual Gbp genes or the entire Gbp gene cluster on mouse chromosome 3. Individual Gbp deletion strains differ in their design, as some strains exist on a pure C57BL/6 genetic background, while other strains contain a 129-derived genetic interval encompassing the Gbp gene cluster on an otherwise C57BL/6 genetic background. Methods: To determine whether the presence of 129 alleles of paralogous Gbps could influence the phenotypes of 129-congenic Gbp-deficient strains, we studied the expression of Gbps in both C57BL/6J and 129/Sv mice following in vivo stimulation with adjuvants and after infection with either Toxoplasma gondii or Shigella flexneri. Results: We show that C57BL/6J relative to 129/Sv mice display moderately elevated expression of Gbp2, but more prominently, are also defective for Gbp2b (formerly Gbp1) mRNA induction upon immune priming. Notably, Toxoplasma infections induce robust Gbp2b protein expression in both strains of mice, suggestive of a Toxoplasma-activated mechanism driving Gbp2b protein translation. We further find that the higher expression of Gbp2b mRNA in 129/Sv mice correlates with a gene duplication event at the Gbp2b locus resulting in two copies of the Gbp2b gene on the haploid genome of the 129/Sv strain. Conclusions: Our findings demonstrate functional differences between 129 and C57BL/6 Gbp alleles which need to be considered in the design and interpretation of studies utilizing mouse models, particularly for phenotypes influenced by Gbp2 or Gbp2b expression.

Differential Maintenance and Frequency-Dependent Tuning of LTP at Hippocampal Synapses of Specific Strains of Inbred Mice

2000 ◽  
Vol 84 (5) ◽  
pp. 2484-2493 ◽  
Author(s):  
Peter V. Nguyen ◽  
Steven N. Duffy ◽  
Jennie Z. Young
Keyword(s):  
Genetic Background ◽  
Pyramidal Neurons ◽  
Inbred Mice ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Synaptic Facilitation ◽  
Ca1 Pyramidal Neurons ◽  
Hippocampal Synapses ◽  
Strain Dependent

Transgenic and knockout mice are used extensively to elucidate the molecular mechanisms of hippocampal synaptic plasticity. However, genetic and phenotypic variations between inbred mouse strains that are used to construct genetic models may confound the interpretation of cellular neurophysiological data derived from these models. Using in vitro slice stimulation and recording methods, we compared the membrane biophysical, cellular electrophysiological, and synaptoplastic properties of hippocampal CA1 neurons in four specific strains of inbred mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms/J. Hippocampal long-term potentiation (LTP) induced by theta-pattern stimulation, and by repeated multi-burst 100-Hz stimulation at various interburst intervals, was better maintained in area CA1 of slices from BL/6J mice than in slices from CBA and DBA mice. At an interburst interval of 20 s, maintenance of LTP was impaired in CBA and DBA slices, as compared with BL/6J slices. When the interburst interval was reduced to 3 s, induction of LTP was significantly enhanced in129/SvEms slices, but not in DBA and CBA slices. Long-term depression (LTD) was not significantly different between slices from these four strains. For the four strains examined, CA1 pyramidal neurons showed no significant differences in spike-frequency accommodation, membrane input resistance, and number of spikes elicited by current injection. Synaptically-evoked glutamatergic postsynaptic currents did not significantly differ among CA1 pyramidal neurons in these four strains. Since the observed LTP deficits resembled those previously seen in transgenic mice with reduced hippocampal cAMP-dependent protein kinase (PKA) activity, we searched for possible strain-dependent differences in cAMP-dependent synaptic facilitation induced by forskolin (an activator of adenylate cyclase) and IBMX (a phosphodiesterase inhibitor). We found that forskolin/IBMX-induced synaptic facilitation was deficient in area CA1 of DBA/2J and CBA/J slices, but not in BL/6J and 129/SvEms/J slices. These defects in cAMP-induced synaptic facilitation may underlie the deficits in memory, observed in CBA/J and DBA/2J mice, that have been previously reported. We conclude that hippocampal LTP is influenced by genetic background and by the temporal characteristics of the stimulation protocol. The plasticity of hippocampal synapses in some inbred mouse strains may be “tuned” to particular temporal patterns of synaptic activity. From a broader perspective, our data support the notion that strain-dependent variation in genetic background is an important factor that can influence the synaptoplastic phenotypes observed in studies that use genetically modified mice to explore the molecular bases of synaptic plasticity.

Impact of genetic background on nephropathy in diabetic mice

2006 ◽  
Vol 290 (1) ◽  
pp. F214-F222 ◽  
Author(s):  
Susan B. Gurley ◽  
Sharon E. Clare ◽  
Kamie P. Snow ◽  
Ann Hu ◽  
Timothy W. Meyer ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Genetic Background ◽  
Structural Changes ◽  
Inbred Mouse ◽  
Renal Involvement ◽  
Model Development ◽  
Mouse Strains ◽  
General Character ◽  
Mesangial Expansion ◽  
Akita Mice

With the goal of identifying optimal platforms for developing better models of diabetic nephropathy in mice, we compared renal effects of streptozotocin (STZ)-induced diabetes among five common inbred mouse strains (C57BL/6, MRL/Mp, BALB/c, DBA/2, and 129/SvEv). We also evaluated the renal consequences of chemical and genetic diabetes on the same genetic background (C57BL/6). There was a hierarchical response of blood glucose level to the STZ regimen among the strains (DBA/2 > C57BL/6 > MRL/MP > 129/SvEv > BALB/c). In all five strains, males demonstrated much more robust hyperglycemia with STZ than females. STZ-induced diabetes was associated with modest levels of albuminuria in all of the strains but was greatest in the DBA/2 strain, which also had the most marked hyperglycemia. Renal structural changes on light microscopy were limited to the development of mesangial expansion, and, while there were some apparent differences among strains in susceptibility to renal pathological changes, there was a significant positive correlation between blood glucose and the degree of mesangial expansion, suggesting that most of the variability in renal pathological abnormalities was because of differences in hyperglycemia. Although the general character of renal involvement was similar between chemical and genetic diabetes, Akita mice developed more marked hyperglycemia, elevated blood pressures, and less variability in renal structural responses. Thus, among the strains and models tested, the DBA/2 genetic background and the Akita ( Ins2+/C96Y) model may be the most useful platforms for model development.

Low-vitamin E diet exacerbates calcium oxalate crystal formation via enhanced oxidative stress in rat hyperoxaluric kidney

2009 ◽  
Vol 296 (1) ◽  
pp. F34-F45 ◽  
Author(s):  
Ho-Shiang Huang ◽  
Ming-Chieh Ma ◽  
Jun Chen
Keyword(s):  
Oxidative Stress ◽  
Drinking Water ◽  
Vitamin E ◽  
Calcium Oxalate ◽  
Oxidative Enzyme ◽  
Separate Experiment ◽  
Crystal Formation ◽  
Standard Diet ◽  
Crystal Deposition ◽  
Caox Crystal

Vitamin E was previously reported to reduce calcium oxalate (CaOx) crystal formation. This study explored whether vitamin E deficiency affects intrarenal oxidative stress and accelerates crystal deposition in hyperoxaluria. The control (C) group of rats received a standard diet and drinking water, while the experimental groups received 0.75% ethylene glycol (EG) in drinking water for 42 days. Of the latter, one group received a standard diet (EG group), one received a low-vitamin E (LE) diet (EG+LE group), and the last received an LE diet with vitamin E supplement (4 mg) (EG+LE+E group). The C+LE and C+LE+E groups were the specific controls for the last two experimental groups, respectively. In a separate experiment, EG and EG+LE rats were studied on days 3–42 to examine the temporal relationship between oxidative change and crystal formation. Urinary biochemistry and activity/levels of antioxidative and oxidative enzymes in glomeruli and tubulointerstitial specimens (TIS) were examined. In EG rats, CaOx crystal accumulation was associated with low antioxidative enzyme activity in TIS and with increased oxidative enzyme expression in glomeruli. In the EG+LE group, marked changes in antioxidative and oxidative enzyme levels were seen and correlated with massive CaOx deposition and tubular damage. The increased oxidative stress seen with EG+LE treatment was largely reversed by vitamin E supplementation. A temporal study showed that decrease in antioxidative defense and increased free radical formation in the EG+LE group occurred before crystal deposition. This study shows that low vitamin E disrupts the redox balance and causes cell death, thereby favoring crystal formation.

Strain differences in urinary factors that promote calcium oxalate crystal formation in the kidneys of ethylene glycol-treated rats

2009 ◽  
Vol 296 (5) ◽  
pp. F1080-F1087 ◽  
Author(s):  
Yan Li ◽  
Kenneth E. McMartin
Keyword(s):  
Ethylene Glycol ◽  
Calcium Oxalate ◽  
Wistar Rats ◽  
Kidney Tissue ◽  
Wistar Rat ◽  
Crystal Formation ◽  
Rat Strains ◽  
Crystal Deposition ◽  
Caox Crystal ◽  
F344 Rats

Ethylene glycol (EG)-induced hyperoxaluria is the most commonly employed experimental regimen as an animal model of calcium oxalate (CaOx) stone formation. The variant sensitivity to CaOx among different rat strains has not been fully explored, although the Wistar rat is known to accumulate more CaOx in kidney tissue after low-dose EG exposure than in the Fischer 344 (F344) rats. Supersaturation of CaOx in tubular fluid contributes to the amount of CaOx crystal formation in the kidney. We hypothesized that the urinary supersaturation of CaOx in Wistar rats is higher than that of F344 rats, thereby allowing for greater CaOx crystal deposition in the Wistar rat. Age-matched male Wistar and F344 rats were treated with 0.75% EG or drinking water for 8 wk. Twenty-four-hour urine was collected at 0, 2, 4, 6, and 8 wk for analysis of key electrolytes to calculate the CaOx supersaturation. Plasma oxalate level was also measured. Our data confirmed the different sensitivity to renal toxicity from EG between the two rat strains (Wistar > F344). After EG treatment, the plasma oxalate level and urine oxalate excretion were markedly greater in the Wistar rats than in the F344 rats, while urine calcium was slightly decreased in Wistars. Thus, the CaOx supersaturation in urine of Wistar rats was higher, which led to a greater crystal deposition in kidney in Wistar rats. These studies suggest that during EG treatment, changes in urine electrolytes and in CaOx supersaturation occur to a greater extent in the Wistar rat, in agreement with its greater sensitivity to EG toxicity.

scholarly journals Comparison of Adult Hippocampal Neurogenesis and Susceptibility to Treadmill Exercise in Nine Mouse Strains

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Jong Whi Kim ◽  
Sung Min Nam ◽  
Dae Young Yoo ◽  
Hyo Young Jung ◽  
Il Yong Kim ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Genetic Background ◽  
Granule Cells ◽  
Treadmill Exercise ◽  
Inbred Mouse ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Mouse Strains ◽  
Neuroblast Differentiation ◽  
Outbred Mouse

The genetic background of mice has various influences on the efficacy of physical exercise, as well as adult neurogenesis in the hippocampus. In this study, we investigated the basal level of hippocampal neurogenesis, as well as the effects of treadmill exercise on adult hippocampal neurogenesis in 9 mouse strains: 8 very commonly used laboratory inbred mouse strains (C57BL/6, BALB/c, A/J, C3H/HeJ, DBA/1, DBA/2, 129/SvJ, and FVB) and 1 outbred mouse strain (ICR). All 9 strains showed diverse basal levels of cell proliferation, neuroblast differentiation, and integration into granule cells in the sedentary group. C57BL/6 mice showed the highest levels of cell proliferation, neuroblast differentiation, and integration into granule cells at basal levels, and the DBA/2 mice showed the lowest levels. The efficacy of integration into granule cells was maximal in ICR mice. Treadmill exercise increased adult hippocampal neurogenesis in all 9 mouse strains. These results suggest that the genetic background of mice affects hippocampal neurogenesis and C57BL/6 mice are the most useful strain to assess basal levels of cell proliferation and neuroblast differentiation, but not maturation into granule cells. In addition, the DBA/2 strain is not suitable for studying hippocampal neurogenesis.

Chronic l-arginine administration increases oxidative and nitrosative stress in rat hyperoxaluric kidneys and excessive crystal deposition

2008 ◽  
Vol 295 (2) ◽  
pp. F388-F396 ◽  
Author(s):  
Ho-Shiang Huang ◽  
Ming-Chieh Ma ◽  
Jun Chen
Keyword(s):  
Nitrosative Stress ◽  
Tubular Damage ◽  
Crystal Formation ◽  
Oxidative And Nitrosative Stress ◽  
Crystal Deposition ◽  
Caox Crystal ◽  
Diuretic Response ◽  
Crystal Accumulation ◽  
Oxide Synthase ◽  
Nos Isoforms

Hyperoxaluric kidneys show an impaired diuretic response to acute infusion of l-arginine. In this study, we examined the chronic effect of l-arginine supplementation on CaOx crystal formation in hyperoxaluric rat kidneys. Eight groups were tested: control (received drinking water), L group (received l-arginine, 0.6%), LN group [received NG-nitro-l-arginine methyl ester (l-NAME, 10 mg/kg)], L + LN group (received l-arginine + l-NAME), HP group [received hydroxyl-l-proline (HP, 5%) mixed with chow to induce hyperoxaluria], L + HP group (received HP + l-arginine), HP + LN group, and L + HP + LN group. The duration was 42 days, and each group had eight animals. Urinary biochemistry and renal CaOx amounts were measured, as well as renal expressions of nitric oxide synthase (NOS) isoforms and NAD(P)H oxidase. The distribution of inducible NOS (iNOS), NAD(P)H oxidase, ED1-positive cells, and nitrotyrosine was examined by immunohistochemical and immunofluorescence studies, whereas superoxide production from the kidneys was examined by fluorescence spectrometric assay. Compared with the HP group, the L + HP group had excessive CaOx crystal accumulation and enhanced endothelial NOS (eNOS), iNOS, and NAD(P)H oxidase protein expression in the kidney. Urinary excretion of nitrotyrosine was markedly increased. Increased superoxide formation in the L + HP kidney was derived from NAD(P)H oxidase and uncoupled eNOS, and increased nitrotyrosine formation might derive from iNOS and ED1-positive cells that gathered around the CaOx crystals. l-NAME cotreatment (L + HP + LN group) reduced renal oxidative nitrosative stress and tubular damage, which were induced by L + HP. The results showed that chronic l-arginine treatment to the hyperoxaluric kidney with massive CaOx crystal deposition may have a toxic effect by enhancing intrarenal oxidative and nitrosative stress.

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