BACKGROUND:Iron homeostasis in heart is essential for maintaining cardiac function, but its precise role in iron metabolism and its specific function remain incompletely understood. METHODS AND RESULTS:We generated cardiomyocyte-specific Fbxl5 deficient mice (αMHC-Cre;Fbxl5F/F). Those mice showed increased IRP2 protein levels, which in cardiomyocytes undergoes Fbxl5-dependent degradation. Young (12-week-old) αMHC-Cre;Fbxl5F/F mice also showed upregulated levels of the IRP2, target transferrin receptor 1 (TfR1) and enhanced Fe3+ uptake into cardiomyocytes, increasing ferritin, total iron, and Fe2+ levels in cardiomyocytes. Fbxl5 deficiency increased both mitochondrial respiration capacity in isolated cardiac mitochondria and contractility of isolated cardiomyocytes, and in vivo, young αMHC-Cre;Fbxl5F/F mice showed augmented cardiac contractility and improved exercise tolerance. By contrast, in aged (24-month-old) αMHC-Cre;Fbxl5F/F mice, IRP2 levels were elevated relative to controls, but TfR1 upregulation and tissue iron accumulation were not seen. Accordingly, enhanced cardiac contractility and superior exercise tolerance phenotypes seen in young αMHC-Cre;Fbxl5F/F mice were absent in comparably aged mice, which unexpectedly exhibited pathological cardiac hypertrophy and upregulation of heart failure-associated genes. Furthermore, we found that administration of sodium-glucose cotransporter-2 inhibitors (SGLT2i), whose cardioprotective effects have recently been suggested to involve enhanced myocardial iron storage, improved cardiac performance without altering myocardial iron content, suggesting that SGLT2i exerts cardioprotective effects largely independent of cardiac iron metabolism. CONCLUSION:Cardiac iron dynamics are precisely regulated and tightly linked to cardiac function and prolonged dysregulation of iron dynamics can trigger cardiac pathological remodeling, even when iron balance is restored.

Mitochondria play a central role in cellular energy metabolism and homeostasis, and their dysfunction is closely linked to the progression of age-related diseases. The mitochondrial ubiquitin ligase MITOL (also known as MARCHF5) is a key regulator of mitochondrial dynamics and function, and reduced MITOL expression in the mouse heart has been implicated in mitochondrial dysfunction and cardiac aging. In this study, we identified berberrubine as a compound that promotes MITOL expression and activates mitochondria. We further assembled a group of berberrubine-based compounds, including its quinoid form and a newly developed water-soluble derivative, and collectively named them “Mitorubin” as mitochondria-activating compounds with therapeutic potential. While conventional berberrubine has poor water solubility, the addition of acetic acid significantly improved its solubility, enabling formulation as a solution. Mitorubin enhanced MITOL expression in cultured cells, increased mitochondrial DNA content and expression of mitochondrial proteins, and promoted mitochondrial respiration. In a model of age-related cardiac dysfunction, oral administration of Mitorubin restored mitochondrial function, improved cardiac performance, suppressed myocardial hypertrophy, and alleviated pulmonary congestion. Moreover, Mitorubin did not shorten lifespan in aged mice and significantly extended lifespan in high-fat diet-fed mice, suggesting both safety and efficacy under chronic administration. These findings suggest that Mitorubin is a promising mitochondrial activator and may represent a novel therapeutic strategy for age-related diseases.

The discovery of the senescence-associated secretory phenotype (SASP) has reshaped our understanding of cellular senescence, shifting its role from a solely tumor-suppressive mechanism to a potential driver of chronic inflammation and age-related diseases. Accordingly, senolytic drugs, which selectively eliminate senescent cells, have garnered considerable interest due to promising preclinical studies. However, concerns remain regarding the reproducibility and generalizability of these findings. In this cross-laboratory study, we rigorously tested the senolytic efficacy of a GLS1 inhibitor and an anti-PD-1 antibody—agents previously reported to reduce the burden of p16 INK4a -positive senescent cells and improve health outcomes in aged mice. Contrary to earlier reports, our study demonstrates that neither GLS1 inhibition nor PD-1 blockade significantly reduced p16 INK4a -positive cell burden or improved aging-related health parameters. Although we do not seek to discredit prior work, our results underscore the need for rigorous design, standardized protocols, and independent validation to ensure reliable senolytics before clinical translation.

Caloric restriction (CR) has shown the potential to extend lifespan and reduce cancer risk; however, the mechanisms underlying CR-mediated tumor suppression are not fully understood. Here, we investigate age-dependent CR effects on tumor progression and anti-tumor immune responses in a murine CR model. In aged mice, CR, defined as a 30% reduction in caloric intake, significantly suppressed tumor growth in murine syngeneic models of colorectal cancer or melanoma. CR also enhanced tumor infiltration by CD8+ T cells, which when depleted limited the tumor-suppressive effects of CR in aged mice. RNA-seq analysis of intratumoral CD8+ T cells revealed that CR upregulated the expression of genes associated with T cell function. Furthermore, mechanistic studies of effects of CR on age-related changes in CD8+ T cells, and immunohistochemical analysis suggested that normalization of the vasculature in the tumor microenvironment of aged CR mice is accompanied by decreased expression of angiogenic growth factors secreted by intratumoral CD8+ T cells. Our findings overall provide insight into age-dependent tumor-suppressive effects of CR and illustrate the essential role of CD8+ T cells in CR-mediated tumor suppression.

Age-related declines in cardiac function and exercise tolerance interfere with healthy living and decrease healthy life expectancy in older individuals. Tamogi-take mushrooms (Pleurotus cornucopiae) are known to contain high levels of Ergothioneine (EGT), an antioxidant with potential health benefits. In this study, we assessed the possibility that long-term consumption of Tamogi-take mushrooms might attenuate age-related decline in cardiac and vascular endothelial function in mice. We found that long-term intake of Tamogi-take mushrooms significantly maintained cardiac and vascular endothelial function and improved exercise tolerance in mice. Long-term mushroom consumption also increased levels of Nrf2 (Nuclear factor E2-related factor 2) protein in heart tissues and increased translation of HO-1 (Heme Oxygenase 1) proteins, which have antioxidant effects in heart and aortic tissues. Finally, long-term Tamogi-take mushroom consumption inhibited ROS accumulation with aging and reduced expression of inflammatory biomarkers. We conclude that ingestion of Tamogi-take mushrooms could serve as a dietary intervention to promote cardiovascular health, support healthy aging and slow the progression of age-related diseases.

Skin tissue, which consists of epidermal, dermal, and hypodermal cells, plays an important role in biological defense and physical appearance. External and internal stresses occurring with aging disrupt skin homeostasis, promoting the development of phenotypes associated with aging. Although many studies of skin aging focus on the dermis, potential epidermal changes have largely remained uncharacterized. In this study, we demonstrate that epidermal cells do not exhibit cellular senescence phenotypes with aging but instead show age-related decreases in mitochondrial number. We also found that mice lacking TFAM in epidermal cells exhibit delayed hair regrowth and impaired wound healing by middle age, resembling changes seen in skin of aged mice. Furthermore, middle-aged epidermis-specific TFAM-deficient mice exhibited obesity, suggesting that impaired fatty acid metabolism in epidermal cells resulting from mitochondrial decline may lead to obesity. These findings overall suggest that mitochondrial decline occurs as a primary event in epidermal aging and that antiaging strategies to enhance activity or number of epidermal mitochondria could antagonize both skin-aging phenotypes and age-related metabolic disease.

OBJECTIVE:Cardiac function declines with age, impairing exercise tolerance and negatively impacting healthy aging. However, mechanisms driving age-related declines in cardiac function are not fully understood. METHODS:We examined mechanisms underlying age-related cardiac dysfunction using 3- and 24-month-old wild-type mice fed ad libitum or 24-month-old wild-type mice subjected to 70% calorie restriction (CR) starting at 2-month-old. In addition, cardiac aging phenotypes and mitochondrial biogenesis were also analyzed in 25-month-old cardiac-specific Hint1 knockout mice, 24-month-old CAG-Caren Tg mice, and 24-month-old wild-type mice injected with AAV6-Caren. RESULTS:We observed inactivation of mitochondrial biogenesis in hearts of aged mice. We also showed that activity of the BAF chromatin remodeling complex is repressed by HINT1, whose expression in heart increases with age, leading to decreased transcription of Tfam, which promotes mitochondrial biogenesis. Interestingly, CR not only suppressed age-related declines in cardiac function and mitochondrial biogenesis but blocked concomitant increases in cardiac HINT1 protein levels and maintained Tfam transcription. Furthermore, expression of the lncRNA Caren, which inhibits Hint1 mRNA translation, decreased with age in heart, and CR suppressed this effect. Finally, decreased HINT1 expression due to Caren overexpression antagonized age-related declines in mitochondrial biogenesis, ameliorating age-related cardiac dysfunction, exercise intolerance, and exercise-induced cardiac damage and subsequent death of mice. CONCLUSION:Our findings suggest that mitochondrial biogenesis in cardiomyocytes decreases with age and could underlie cardiac dysfunction, and that the Caren-HINT1-mitochondrial biogenesis axis may constitute a mechanism linking CR to resistance to cardiac aging. We also show that ameliorating declines in mitochondrial biogenesis in cardiomyocytes could counteract age-related declines in cardiac function, and that this strategy may improve exercise tolerance and extend so-called "healthy life span".

BACKGROUND:The ability to predict secondary cardiovascular events could improve health of patients undergoing statin treatment. Circulating ANGPTL8 (angiopoietin-like protein 8) levels, which positively correlate with proatherosclerotic lipid profiles, activate the pivotal proatherosclerotic factor ANGPTL3. Here, we assessed potential association between circulating ANGPTL8 levels and risk of secondary cardiovascular events in statin-treated patients. METHODS:We conducted a biomarker study with a case-cohort design, using samples from a 2018 randomized control trial known as randomized evaluation of high-dose (4 mg/day) or low-dose (1 mg/day) lipid-lowering therapy with pitavastatin in coronary artery disease (REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease])." From that study's full analysis set (n=12 413), we selected 2250 patients with stable coronary artery disease (582 with the primary outcome, 1745 randomly chosen, and 77 overlapping subjects). A composite end point including cardiovascular-related death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergent admission was set as a primary end point. Circulating ANGPTL8 levels were measured at baseline and 6 months after randomization. RESULTS:Over a 6-month period, ANGPTL8 level changes significantly decreased in the high-dose pitavastatin group, which showed 19% risk reduction of secondary cardiovascular events compared with the low-dose group in the REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease] study. In the highest quartiles, relative increases in ANGPTL8 levels were significantly associated with increased risk for secondary cardiovascular events, after adjustment for several cardiovascular disease risk factors and pitavastatin treatment (hazard ratio in Q4, 1.67 [95% CI, 1.17-2.39). Subgroup analyses showed relatively strong relationships between relative ANGPTL8 increases and secondary cardiovascular events in the high-dose pitavastatin group (hazard ratio in Q4, 2.07 [95% CI, 1.21-3.55]) and in the low ANGPTL8 group at baseline (166 <pmol/L, hazard ratio in Q4: 1.74, [95% CI, 1.04-2.93]). CONCLUSIONS:Monitoring ANGPTL8 levels over time might be useful to assess residual risk of cardiovascular secondary events in patients with cardiovascular disease undergoing statin therapy.

Previously, we reported that an ANGPTL3 vaccine is a hopeful therapeutic option against dyslipidemia. In our current study, we assess durability and booster effects of that vaccine over a period representing a mouse's lifespan. The vaccine remained effective for over one year, and booster vaccination maintained suppression of circulating triglyceride levels thereafter without major adverse effects on lungs, kidneys, or liver, suggesting vaccine efficacy and safety.

Previous studies show that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) functions as a tumor promoter in some cancer contexts. However, we recently reported that host ANGPTL2 also shows tumor suppressive activity by enhancing dendritic cell-mediated CD8+ T cell anti-tumor immune responses in mouse kidney cancer and murine syngeneic models. However, mechanisms underlying ANGPTL2-mediated tumor suppression are complex and not well known. Here, we investigated ANGPTL2 tumor suppressive function in chemically-induced intestinal tumorigenesis. ANGPTL2 deficiency enhanced intestinal tumor growth in an experimental mouse colitis-associated colon cancer (CAC) model. Angptl2-deficient mice also showed a decrease not only in CD8+ T cell responses but in CD4+ T cell responses during intestinal tumorigenesis. Furthermore, we show that stroma-derived ANGPTL2 can activate the myeloid immune response. Notably, ANGPTL2 drove generation of immunostimulatory macrophages via the NF-κB pathway, accelerating CD4+ T helper 1 (Th1) cell activation. These findings overall provide novel insight into the complex mechanisms underlying ANGPTL2 anti-tumor function in cancer pathology.

Sarcopenia due to loss of skeletal muscle mass and strength leads to physical inactivity and decreased quality of life. The number of individuals with sarcopenia is rapidly increasing as the number of older people increases worldwide, making this condition a medical and social problem. Some patients with sarcopenia exhibit accumulation of peri-muscular adipose tissue (PMAT) as ectopic fat deposition surrounding atrophied muscle. However, an association of PMAT with muscle atrophy has not been demonstrated. Here, we show that PMAT is associated with muscle atrophy in aged mice and that atrophy severity increases in parallel with cumulative doses of PMAT. We observed severe muscle atrophy in two different obese model mice harboring significant PMAT relative to respective control non-obese mice. We also report that denervation-induced muscle atrophy was accelerated in non-obese young mice transplanted around skeletal muscle with obese adipose tissue relative to controls transplanted with non-obese adipose tissue. Notably, transplantation of obese adipose tissue into peri-muscular regions increased nuclear translocation of FoxO transcription factors and upregulated expression FoxO targets associated with proteolysis (Atrogin1 and MuRF1) and cellular senescence (p19 and p21) in muscle. Conversely, in obese mice, PMAT removal attenuated denervation-induced muscle atrophy and suppressed upregulation of genes related to proteolysis and cellular senescence in muscle. We conclude that PMAT accumulation accelerates age- and obesity-induced muscle atrophy by increasing proteolysis and cellular senescence in muscle.

The Hirschsprung disease (HSCR) is an inherited disease that is controlled by multiple genes and has a complicated genetic mechanism. HSCR patients suffer from various extents of constipation due to dysplasia of the enteric nervous system (ENS), which can be so severe as to cause complete intestinal obstruction. Many genes have been identified as playing causative roles in ENS dysplasia and HSCR, among them the endothelin receptor type B gene (Ednrb) has been identified to play an important role. Mutation of Ednrb causes a series of symptoms that include deafness, pigmentary abnormalities, and aganglionosis. In our previous studies of three rat models carrying the same spotting lethal (sl) mutation on Ednrb, the haplotype of a region on chromosome (Chr) 2 was found to be responsible for the differing severities of the HSCR-like symptoms. To confirm that the haplotype of the responsible region on Chr 2 modifies the severity of aganglionosis caused by Ednrb mutation and to recreate a rat model with severe symptoms, we selected the GK inbred strain, whose haplotype in the responsible region on Chr 2 resembles that of the rat strain in which severe symptoms accompany the Ednrbsl mutation. An Ednrb mutation was introduced into the GK rat by crossing with F344-Ednrbsl and by genome editing. The null mutation of Ednrb was found to cause embryonic death in F2 progeny possessing the GK haplotype in the responsible region on Chr 2. The results of this study are unexpected, and they provide new clues and animal models that promise to contribute to studies on the genetic regulatory network in the development of ENS and on embryogenesis.

The resistance/susceptibility to Echinococcus multilocularis infection in mice is genetically controlled. However, genetic factors responsible for these differences remain unknown. Our previous study in genetic linkage analysis has revealed that there is a significant quantitative trait locus (QTL) for the establishment of cyst (Emcys1), and a highly significant QTL for the development of protoscolex of E. multilocularis larvae (Empsc1), on mouse chromosomes 6 and 1, respectively. The current study aimed to confirm these QTLs and narrow down the critical genetic region that controls resistance/susceptibility to E. multilocularis infection by establishing congenic and subcongenic lines from C57BL/6 (B6) and DBA/2 (D2) mice. For protoscolex development phenotype, two congenic lines, B6.D2-Empsc1 and D2.B6-Empsc1 were developed, where responsible QTL, Empsc1 was introgressed from D2 into B6 background and vice versa. For cyst establishment phenotype, two congenic lines, B6.D2-Emcys1 and D2.B6-Emcys1 were developed, where responsible QTL, Emcys1 was introgressed from D2 into B6 background and vice versa. Because there was no significant difference in cyst establishment between B6.D2-Emcys1 and D2.B6-Emcys1 mice after challenge with E. multilocularis, it is suggested that the Emcys1 does not solely control the cyst establishment in mouse liver. However, infection experiments with B6.D2-Empsc1 and D2.B6-Empsc1 mice showed a significant difference in protoscolex development in the cyst. It confirms that the Empsc1 controls phenotype of the protoscolex development in the cyst. Subsequently, two subcongenic lines, B6.D2-Empsc1.1 and B6.D2-Empsc1.2 from B6.D2-Emcys1 and one subcongenic line, D2.B6-Empsc1.1 from D2.B6-Empsc1 were developed to narrow down the critical region responsible for protoscolex development. From the results of infection experiments with E. multilocularis in these subcongenic mice, it is concluded that a gene responsible for protoscolex development is located between D1Mit290 (68.1 cM) and D1Mit511 (97.3 cM).

Sendai virus (SeV) is one of the most important pathogens in the specific-pathogen free rodents. It is known that there are some inbred mouse strains susceptible or resistant to SeV infection. The C57BL/6 (B6) and DBA/2 (D2) mice are representative of the resistant and susceptible strains, respectively. Previous study with the quantitative trait locus (QTL) analysis identified three QTLs responsible for resistance or susceptibility to SeV infection on different chromosomes and indicated that resistance or susceptibility to SeV infection was almost predicted by genotypes of these three QTLs. In this paper, to verify the above hypothesis, congenic lines were generated as follows; B6-congenic lines carrying one of the D2 alleles of three QTLs and combination of these three QTLs, and D2-congenic lines carrying single or combination of B6 alleles of three QTLs. All these congenic lines were then challenged with SeV infection. D2 congenic lines introgressed single or combination of B6 alleles of QTLs changed to resistance to SeV infection. Especially, a D2 triple-congenic line became resistant as similar level to B6-parental strain. However, B6-congenic lines introgressed single or combination of D2 alleles of QTLs all remained to be resistant to SeV infection. Both IL-6 and TNF-α in broncho-alveolar lavage fluid of D2 triple-congenic line were decreased to the similar level of B6 mice, suggesting that this is a part of factors that D2 triple-congenic line became resistant to the similar level of B6 mice. Data obtained from these congenic mice verified that three QTLs identified previously were indeed responsible for the resistance/susceptibility to SeV infection in B6 and D2 mice.

The three different mouse handling methods, picking up by tails, tunnels, and open hands were performed using the ICGN glomerulonephritis mouse and the severity of symptoms was evaluated. The handling groups exhibited a tendency of more severe symptoms than the non-handling control group. Female mice handled by their tails showed significantly more severe symptoms than the control group. In addition, we subjected the normal laboratory mice, C57BL/6 and BALB/c mice to tail and tunnel handling to assess the stress conditions. The plasma corticosterone level in the tail-handled mice was higher than that in control mice. These results indicate that handling causes stress and may affect the phenotype of disease model mice.

The oligoadenylate synthetase (OAS) is well known as an antiviral factor against the flavivirus infection in mammals. It is known that the oligoadenylate synthetase-like (ChOAS-L) gene is only present in the chicken genome. It has been shown in the previous report that the ChOAS-L possesses enzymatic activity to convert ATP into 2'-5'-linked oligoadenylates and antiviral activity against West Nile virus (WNV) replicon. Therefore, this study aimed to investigate the relationship between enzymatic and antiviral activities of ChOAS-L. Eight mutated ChOAS-L proteins were generated using either the site-directed mutagenesis or standard polymerase chain reaction protocol. The wild-type and mutated proteins were ectopically expressed in 293FT cells to analyze the enzymatic activity and in BHK-21 and BALB/3T3 cells to analyze the antiviral activity using WNV replicon. The results revealed that all mutated proteins showed no enzymatic activity except for ChOAS-L-AΔUbL2. However, all mutated proteins showed antiviral activity to inhibit the replication of the WNV replicon except for ChOAS-L-AΔUbL1/UbL2, which showed a partial inhibition compared to the wild-type ChOAS-L-A or other mutated proteins. These results suggest that the ChOAS-L expresses the antiflavivirus activity in a manner independent of enzymatic activity. Our results propose reconsideration of the mechanism of antiviral activity against the flavivirus replication of ChOAS-L.

The interferon-induced oligoadenylate synthetase (OAS) family is one of the most important immune response proteins to the viral infection. The OAS protein binds dsRNA and is activated to produce 2',5'-oligoadenylates, which lead to the activation of latent form of RNase L, resulting in degradation of cellular and viral RNA and inhibition of viral replication. In mice, the Oas gene family locates on chromosome 5. The mouse Oas gene locus undergoes a recent series of duplication event, leading to the presence of eight paralogs of Oas1 genes (Oas1a through Oas1h) that forms Oas gene cluster with the Oas2, Oas3 and two OasL (OasL1 and OasL2) genes. Previous studies demonstrated that the mouse Oas1b gene conferred resistance to the flavivirus infection in mice; however, the antiviral activity of other mouse Oas1 gene family is still unknown. Therefore, in the present study, we have evaluated the mouse Oas1 paralogs regarding the enzymatic activity and antiviral activity against the two neurotropic flaviviruses, West Nile virus and tick-borne encephalitis virus. The mouse Oas1 genes were cloned from C57BL/6J (B6) as well as the Oas1b derived from feral mouse strain, MSM. The obtained results demonstrated that only Oas1a and Oas1g showed enzymatic activity. Although MSM-derived Oas1b showed antiviral activity to both viruses, all B6-derived OAS paralogs did not show antiviral activity. These results suggest that Oas1a and Oas1g play a role in potentiating viral RNA-induced interferon response in the cell, whereas the Oas1b works as a specific anti-flavivirus factor unless it is mutated. However, the role of other paralogs is unknown and should wait for further investigation.

Pigmentary variation in animals has been studied because of its application in genetics, evolution and developmental biology. The large number of known color loci provides rich resource to elucidate the functional pigmentary system. Nonetheless, more color loci remain to be identified. In our previous study, we revealed that two different strains, namely, AGH rats and LEH rats, but which had the same null mutation of the Ednrb gene ( Ednrb sl ) showed markedly different pigmented coat ratio. This result strongly suggested that the severity of pigment abnormality was modified by genetic factor(s) in each strain. To elucidate the modifier locus of pigment disorder, we carried out whole-genome scanning for quantitative trait loci (QTLs) on 149 F 2 (AGH- Ednrb sl × LEH- Ednrb sl ) rats. A highly significant QTL, constituting 26% of the total pigmentation phenotype variance, was identified in a region around D7Got23 on chromosome (Chr) 7. In addition, investigation on epistatic interaction revealed significant interactions between D7Got23 and D3Rat78 and between D7Got23 and D14Mit4 . Results suggested that a modified locus on Chr 7 was mainly responsible for the variance of pigmentary disorder between AGH- Ednrb sl rats and LEH- Ednrb sl rats and two modifier loci showing epistatic interaction may, in part, influence pigment phenotype.

Depression is one of the most famous psychiatric disorders in humans in all over the countries and considered a complex neurobehavioral trait and difficult to identify causal genes. Tail suspension test (TST) and forced swimming test (FST) are widely used for assessing depression-like behavior and antidepressant activity in mice. A variety of antidepressant agents are known to reduce immobility time in both TST and FST. To identify genetic determinants of immobility duration in both tests, we analyzed 101 F2 mice from an intercross between C57BL/6 and DBA/2 strains. Quantitative trait locus (QTL) mapping using 106 microsatellite markers revealed three loci (two significant and one suggestive) and five suggestive loci controlling immobility time in the TST and FST, respectively. Results of QTL analysis suggest a broad description of the genetic architecture underlying depression, providing underpinnings for identifying novel molecular targets for antidepressants to clear the complex genetic mechanisms of depressive disorders.

Tensin2 (Tns2) is thought to be a component of the cytoskeletal structures linking actin filaments with focal adhesions and is known to play a role as an intracellular signal transduction mediator through integrin in podocytes, although the mechanism by which it functions remains unclear. A Tns2-null mutation (nph) leads to massive albuminuria following podocyte foot process effacement in the ICGN mice, the origin of the mutation, and the DBA/2J (D2) mice, but not in the C57BL/6J (B6) mice or 129(+Ter)/SvJcl (129T) mice. Elucidating the reasons for these differences in diverse genetic backgrounds could help in unraveling Tns2 function in podocytes. We produced congenic mice in which Tns2(nph) was introgressed into a FVB/NJ background (FVB-Tns2(nph)), and evaluated the progression of kidney disease. FVB-Tns2(nph) mice developed albuminuria, renal fibrosis and renal anemia as seen in ICGN mice. The FVB-Tns2(nph) mice demonstrated podocyte foot process alteration under an electron microscope by as early as 4 weeks of age. This revealed that FVB strain is susceptible to Tns2-deficiency.