Alterations in the gene expression of SARS-COV-2 entry receptors and enzymes in lungs and hearts of controlled and uncontrolled diabetic mice

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology Pub Date : 2023-11-10 DOI:10.1111/fcp.12964

Ohood Alkhawaldeh, Yazun Jarrar, Munir Gharaibeh, Sara Abudahab, Dina Abulebdah, Bashir Jarrar

{"title":"Alterations in the gene expression of SARS-COV-2 entry receptors and enzymes in lungs and hearts of controlled and uncontrolled diabetic mice","authors":"Ohood Alkhawaldeh, Yazun Jarrar, Munir Gharaibeh, Sara Abudahab, Dina Abulebdah, Bashir Jarrar","doi":"10.1111/fcp.12964","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>The entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell is carried out by specific receptors and enzymes, including human angiotensin-converting enzyme 2 receptor (ACE2), transmembrane serine protease 2 (TMPRSS2), and cathepsin-L (CTSL). COVID-19 patients with comorbidities, such as diabetes mellitus (DM), are more prone to severe symptoms and have a higher risk of mortality.</p>\n </section>\n \n <section>\n \n <h3> Aims</h3>\n \n <p>The present study aimed to investigate the impact of controlled and uncontrolled type 1 DM (T1DM) on the gene expression of mouse <i>Ace2</i>, <i>Tmprss2</i>, and <i>Ctsl</i> and correlate it with the pathological alterations in the lungs and the heart of DM mice.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Balb/c mice were administered a single dose of 240 mg/kg streptozocin to induce T1DM. The blood glucose level was measured to confirm the induction of DM. Normalization of blood glucose levels in T1DM mice was achieved using 0.1 mL/kg Mixtard® insulin therapy. The mice's lungs and hearts were harvested, and the mRNA was extracted and converted to cDNA. The gene expression of <i>Ace2</i>, <i>Tmprss2</i>, <i>Ctsl</i>, <i>Cyp4a11</i>, and <i>Adrb1</i> genes, which play a role in the homeostasis of lungs and hearts, were measured using quantitative real-time polymerase chain reaction (RT-PCR). The pathological alterations in the hearts and lungs induced by T1DM were evaluated using the relative heart and lung weights, in addition to the pathohistological examination.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>After inducing T1DM for 14 days, we observed a significant reduction in the total weight of uncontrolled DM (UDM) mice (<i>P</i> < 0.05). Pathohistological examination of UDM lung tissues revealed thickening of the alveolar walls with narrowing of the surface of the alveolar sacs. Additionally, we found that UDM mice exhibited downregulation of <i>Ace2</i> gene expression (<i>P</i> < 0.05) in their lungs, while both UDM and control DM (CDM) mice showed upregulation of <i>Ctsl</i> gene expression in their hearts (<i>P</i> < 0.05). Notably, <i>Cyp4a12</i> gene expression was significantly downregulated (<i>P</i> < 0.05) in UDM mice but returned to normal levels in CDM mice.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>We conclude from this study that T1DM downregulates <i>Ace2</i> receptor and <i>Cyp4a12</i> gene expression, which is correlated with the thickening of alveolar walls and narrowing of the surface of alveolar sacs in the lungs. Insulin administration for controlling T1DM ameliorated these pathological alterations. These results can help increase our understanding of the impact of controlled and uncontrolled T1DM on the lungs and may explain, at least in part, why DM patients with COVID-19 experience exacerbation of symptoms.</p>\n </section>\n </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.1000,"publicationDate":"2023-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Fundamental & Clinical Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/fcp.12964","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

The entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell is carried out by specific receptors and enzymes, including human angiotensin-converting enzyme 2 receptor (ACE2), transmembrane serine protease 2 (TMPRSS2), and cathepsin-L (CTSL). COVID-19 patients with comorbidities, such as diabetes mellitus (DM), are more prone to severe symptoms and have a higher risk of mortality.

Aims

The present study aimed to investigate the impact of controlled and uncontrolled type 1 DM (T1DM) on the gene expression of mouse Ace2, Tmprss2, and Ctsl and correlate it with the pathological alterations in the lungs and the heart of DM mice.

Methods

Balb/c mice were administered a single dose of 240 mg/kg streptozocin to induce T1DM. The blood glucose level was measured to confirm the induction of DM. Normalization of blood glucose levels in T1DM mice was achieved using 0.1 mL/kg Mixtard® insulin therapy. The mice's lungs and hearts were harvested, and the mRNA was extracted and converted to cDNA. The gene expression of Ace2, Tmprss2, Ctsl, Cyp4a11, and Adrb1 genes, which play a role in the homeostasis of lungs and hearts, were measured using quantitative real-time polymerase chain reaction (RT-PCR). The pathological alterations in the hearts and lungs induced by T1DM were evaluated using the relative heart and lung weights, in addition to the pathohistological examination.

Results

After inducing T1DM for 14 days, we observed a significant reduction in the total weight of uncontrolled DM (UDM) mice (P < 0.05). Pathohistological examination of UDM lung tissues revealed thickening of the alveolar walls with narrowing of the surface of the alveolar sacs. Additionally, we found that UDM mice exhibited downregulation of Ace2 gene expression (P < 0.05) in their lungs, while both UDM and control DM (CDM) mice showed upregulation of Ctsl gene expression in their hearts (P < 0.05). Notably, Cyp4a12 gene expression was significantly downregulated (P < 0.05) in UDM mice but returned to normal levels in CDM mice.

Conclusions

We conclude from this study that T1DM downregulates Ace2 receptor and Cyp4a12 gene expression, which is correlated with the thickening of alveolar walls and narrowing of the surface of alveolar sacs in the lungs. Insulin administration for controlling T1DM ameliorated these pathological alterations. These results can help increase our understanding of the impact of controlled and uncontrolled T1DM on the lungs and may explain, at least in part, why DM patients with COVID-19 experience exacerbation of symptoms.

查看原文本刊更多论文

受控和非受控糖尿病小鼠肺和心脏中严重急性呼吸系统综合征冠状病毒2型进入受体和酶的基因表达变化。

背景：严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）进入宿主细胞是通过特定的受体和酶进行的，包括人血管紧张素转换酶2受体（ACE2）、跨膜丝氨酸蛋白酶2（TMPRSS2）和组织蛋白酶-L（CTSL）。患有糖尿病（DM）等合并症的新冠肺炎患者更容易出现严重症状，死亡风险更高。目的：本研究旨在研究控制型和非控制型1型糖尿病（T1DM）对小鼠Ace2、Tmprss2和Ctsl基因表达的影响，并将其与DM小鼠肺和心脏的病理变化联系起来。方法：Balb/c小鼠单次给药240 mg/kg链脲佐菌素诱导T1DM。测量血糖水平以确认糖尿病的诱导。使用0.1 mL/kg Mixtard®胰岛素治疗实现了T1DM小鼠血糖水平的正常化。采集小鼠的肺和心脏，提取mRNA并转化为cDNA。使用定量实时聚合酶链式反应（RT-PCR）测量在肺和心脏稳态中起作用的Ace2、Tmprss2、Ctsl、Cyp4a11和Adrb1基因的基因表达。除了病理学检查外，还使用相对心肺重量评估T1DM诱导的心肺病理变化。结果：诱导T1DM 14天后天，我们观察到未受控制的糖尿病（UDM）小鼠的总重量显著减轻（P结论：我们从这项研究中得出结论，T1DM下调了Ace2受体和Cyp4a12基因的表达，这与肺泡壁增厚和肺泡囊表面变窄有关。控制T1DM的胰岛素给药改善了这些病理改变。这些结果有助于加深我们对控制和肺部未控制的T1DM，至少部分解释了新冠肺炎DM患者症状恶化的原因。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Fundamental & Clinical Pharmacology 医学-药学

CiteScore

5.30

自引率

6.90%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.