bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2021.11.27.470203

Development and characterization of a high fat diet-streptozotocin induced type 2 diabetes model in nude athymic rats

Sun, X.·Nunes, S. S.
View original source ↗Export metadata ↓

Abstract

People with diabetes mellitus (DM) are at an increased risk for myocardial infarction (MI) than age matched people without DM. However, assays for pre-clinical therapy are performed in animal models of ischemia that lack the co-morbid conditions present in patients with MI, such as DM. This contributes to the failure to translate pre-clinical trials results to the clinic. Thus, to increase the clinical relevance of xenograft studies in pre-clinical models, it is important to have a DM model in animals that are immunodeficient. Here, we developed a type 2 diabetes mellitus (T2D) model in nude athymic rats using high-fat diet and streptozotocin (HFD-STZ). Nude athymic rats were randomized into a control group (normal chow) or a HFD (45% fat, 20% protein and 35% carbohydrate)-STZ group. STZ (35 mg/kg i.v.) or vehicle was administered 8 weeks after HFD feeding started. Assessments were done longitudinally and at week 9 (endpoint). The HFD-STZ group showed mild hyperglycemia pre STZ administration (7.7 {+/-} 0.3 mM vs 5.8 {+/-} 0.2 mM in control) by week 8. In addition, plasma insulin levels were increased and the HOMA index was 2.5-times higher in the HFD-STZ. The HFD-STZ group showed increased fasting (147%) triglycerides. After STZ-administration, blood glucose levels increased substantially (23.6 {+/-} 1.4 mM vs 5.5 {+/-} 0.3 mM in control). The HFD-STZ treated animals also showed increased left ventricular wall thickness, cardiac hypertrophy and fibrosis, reduced cardiac function compared to normal chow control. In line with the HFD-STZ model in immunocompetent rats, the HFD-STZ treatment of athymic rats recapitulates key features of T2D, including aspects of established clinical diabetic cardiomyopathy and should be suitable for xenograft studies in the context of T2D.

Explore related subjects

pathologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Sun, X., Nunes, S. S.. 2021-11-28. Development and characterization of a high fat diet-streptozotocin induced type 2 diabetes model in nude athymic rats. https://doi.org/10.1101/2021.11.27.470203

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

NAE1-Dependent Protein Neddylation Preserves Endothelial Identity and Vascular Integrity

Background: Endothelial dysfunction is a central driver of cardiovascular and inflammatory diseases, yet the post-translational mechanisms that preserve endothelial homeostasis remain incompletely understood. Protein neddylation, the covalent conjugation of a ubiquitin-like modifier, regulates diverse cellular processes, yet its physiological role in the vascular endothelium remains unknown. This study investigated whether protein neddylation is required to preserve endothelial identity and vascular homeostasis. Methods: We generated tamoxifen-inducible endothelial-specific Nae1 knockout mice to inhibit neddylation and combined bulk RNA sequencing, single-cell and single-nucleus transcriptomics, quantitative proteomics, biochemical analyses, and gain- and loss-of-function approaches to define the role of endothelial neddylation in vascular homeostasis and inflammatory injury. Results: Endothelial-specific Nae1 deletion caused rapid mortality associated with vascular leakage, platelet accumulation, inflammation, and multi-organ injury. Multi-omics analyses demonstrated profound loss of endothelial identity, characterized by suppression of core endothelial programs and activation of inflammatory, procoagulant, and pyroptotic pathways. Single-cell analyses revealed progressive endothelial dysfunction culminating in depletion of the endothelial population and remodeling of the vascular niche. Mechanistically, endothelial neddylation deficiency activated gasdermin D (GSDMD)- and gasdermin E (GSDME)-dependent pyroptosis, whereas dual inhibition of GSDMD and GSDME markedly attenuated inflammatory transcriptomic remodeling, vascular injury, hepatocyte death, immune cell infiltration, and platelet accumulation. Translational analyses demonstrated reduced endothelial neddylation in experimental endotoxemia and decreased expression of neddylation pathway components in human atherosclerosis and COVID-19 datasets. Conversely, restoration of endothelial neddylation partially reversed inflammatory endothelial transcriptomic reprogramming in vivo. Conclusions: NAE1-dependent protein neddylation is an essential regulator of endothelial identity and vascular integrity. Loss of endothelial neddylation promotes gasdermin-dependent pyroptosis and thrombo-inflammatory vascular injury, whereas restoration of the neddylation pathway mitigates inflammatory endothelial dysfunction. These findings identify endothelial neddylation as a fundamental mechanism maintaining vascular homeostasis and a potential therapeutic target for cardiovascular and inflammatory diseases.

pathology↗
bioRxiv2023

Repetitive Sulfur Dioxide Exposure in Mice Models Post-Deployment Respiratory Syndrome

Soldiers deployed to Iraq and Afghanistan have a higher prevalence of respiratory symptoms than non-deployed military personnel and some have been shown to have a constellation of findings on lung biopsy termed post-deployment respiratory syndrome (PDRS). Since many of the deployers in this cohort reported exposure to sulfur dioxide (SO2), we developed a model of repetitive exposure to SO2 in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular disease (PVD). Although abnormalities in small airways were not sufficient to alter lung mechanics, PVD was associated with the development of pulmonary hypertension and reduced exercise tolerance in SO2 exposed mice. Further, we used pharmacologic and genetic approaches to demonstrate a critical role for oxidative stress and isolevuglandins in mediating PVD in this model. In summary, our results indicate that repetitive SO2 exposure recapitulates many aspects of PDRS and that oxidative stress may mediate PVD in this model, which may be helpful for future mechanistic studies examining the relationship between inhaled irritants, PVD, and PDRS.

pathology↗
bioRxiv2023

Jamestown Canyon Virus is transmissible by Aedes aegypti and is only moderately blocked by Wolbachia co-infection

Jamestown Canyon Virus (JCV), a negative-sense arbovirus, is increasingly common in the upper Midwest of the USA. Transmitted by a range of mosquito genera, JCV has at its primary amplifying host, white-tailed deer. Aedes aegypti is the major transmitter globally of the positive-sense viruses dengue (DENV), Zika, chikungunya, and Yellow Fever. Ae. aegyptis distribution, once confined to the tropics, is expanding, in part due to climate change. Wolbachia, an insect endosymbiont, limits the replication of co-infecting viruses inside insects. The release and spread of the symbiont into Ae. aegypti populations has been effective in reducing transmission of dengue and other viruses to humans. The mechanism of Wolbachia-mediated viral blocking in vectors is still poorly understood, however. Here we explored JCV infection potential in Ae. aegypti, the nature of the vectors immune response, and interactions with Wolbachia infection. We show that Ae. aegypti is highly competent for JCV, growing to substantial loads and rapidly reaching the saliva after an infectious blood meal. The mosquito immune system responds with strong induction of RNAi and JAK/STAT. Neither the direct effect of viral infection nor the energetic investment in immunity appears to affect mosquito longevity. Wolbachia infection blocked JCV only in the early stages of infection. Wolbachia-induced immunity was small compared to that of JCV, suggesting innate immune priming does not likely explain blocking. We propose two models to explain why Wolbachias blocking of negative-sense viruses like JCV may be less than that of positive-sense viruses, relating to the slowdown of host protein synthesis and the triggering of interferon-like factors like Vago. In conclusion, we highlight the risk for increased human disease with the predicted future overlap of Ae. aegypti and JCV ranges. We suggest that with moderate Wolbachia-mediated blocking and distinct biology, negative-sense viruses represent a fruitful comparator model to other viruses for understanding blocking mechanisms in mosquitoes. Author SummaryJamestown Canyon Virus (JCV), a newly emerging virus in North America, causes disease when it spills out of its wild mammal hosts into human populations via the bite of infected mosquitoes. We show that the mosquito Aedes aegypti, known for transmitting many viral pathogens to humans globally, and whose distribution is creeping northward in the USA toward regions where JCV is present, is likely able to transmit the virus. Wolbachia is an endosymbiotic bacterium being released in wild mosquito populations of mosquitoes because it limits the replication of human viruses inside the mosquito, limiting their transmission to humans. We show that Wolbachia has a limited ability to control the replication of JCV, which is likely because Wolbachia-induced antiviral response is quite weak, and unique aspects of negative-sense virus biology make them less susceptible to blocking. Our findings suggest that JCV may serve as a comparative model to positive-sense viruses like dengue in dissecting the mechanism of Wolbachia-mediated virus blocking. It also warns that shifting mosquito distributions, as expected under a changing climate, could bring JCV and Aedes mosquitoes into greater contact, potentially increasing the incidence of JCV in humans.

pathology↗