Angiotensin-converting enzyme 2 (ACE2) gene and protein expression in diabetic patients without nephropathy

We investigated the effects of dual renin-angiotensin system (RAS) blockade on angiotensin-converting enzyme-2 (Ace2) expression, hypertension, and renal proximal tubular cell (RPTC) apoptosis in type 1 diabetic Akita angiotensinogen (Agt)-transgenic (Tg) mice that specifically overexpress Agt in their RPTCs. Adult (11 wk old) male Akita and Akita Agt-Tg mice were treated with two RAS blockers (ANG II receptor type 1 blocker losartan, 30 mg·kg−1·day−1) and angiotensin-converting enzyme (ACE) inhibitor perindopril (4 mg·kg−1·day−1) in drinking water. Same-age non-Akita littermates and Agt-Tg mice served as controls. Blood pressure, blood glucose, and albuminuria were monitored weekly. The animals were euthanized at age 16 wk. The left kidneys were processed for immunohistochemistry and apoptosis studies. Renal proximal tubules were isolated from the right kidneys to assess gene and protein expression. Urinary ANG II and ANG 1–7 were quantified by ELISA. RAS blockade normalized renal Ace2 expression and urinary ANG 1–7 levels (both of which were low in untreated Akita and Akita Agt-Tg), prevented hypertension, albuminuria, tubulointerstitial fibrosis and tubular apoptosis, and inhibited profibrotic and proapoptotic gene expression in RPTCs of Akita and Akita Agt-Tg mice compared with non-Akita controls. Our results demonstrate the effectiveness of RAS blockade in preventing intrarenal RAS activation, hypertension, and nephropathy progression in diabetes and support the important role of intrarenal Ace2 expression in modulating hypertension and renal injury in diabetes.

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Replication-dependent downregulation of cellular angiotensin-converting enzyme 2 protein expression by human coronavirus NL63

Journal of General Virology ◽

10.1099/vir.0.043919-0 ◽

2012 ◽

Vol 93 (9) ◽

pp. 1924-1929 ◽

Cited By ~ 63

Author(s):

Ronald Dijkman ◽

Maarten F. Jebbink ◽

Martin Deijs ◽

Aleksandra Milewska ◽

Krzysztof Pyrc ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Protein Expression ◽

Protein Level ◽

Converting Enzyme ◽

Human Coronavirus ◽

Angiotensin Converting Enzyme 2 ◽

Expression Levels ◽

Suboptimal Temperature ◽

Severity Of Disease

Like severe acute respiratory syndrome coronavirus (SARS-CoV), human coronavirus (HCoV)-NL63 employs angiotensin-converting enzyme 2 (ACE2) as a receptor for cellular entry. SARS-CoV infection causes robust downregulation of cellular ACE2 expression levels and it has been suggested that the SARS-CoV effect on ACE2 is involved in the severity of disease. We investigated whether cellular ACE2 downregulation occurs at optimal replication conditions of HCoV-NL63 infection. The expression of the homologue of ACE2, the ACE protein not used as a receptor by HCoV-NL63, was measured as a control. A specific decrease for ACE2 protein level was observed when HCoV-NL63 was cultured at 34 °C. Culturing the virus at the suboptimal temperature of 37 °C resulted in low replication of the virus and the effect on ACE2 expression was lost. We conclude that the decline of ACE2 expression is dependent on the efficiency of HCoV-NL63 replication, and that HCoV-NL63 and SARS-CoV both affect cellular ACE2 expression during infection.

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Gene transfer of angiotensin-converting enzyme 2 in the nucleus tractus solitarius improves baroreceptor heart rate reflex in spontaneously hypertensive rats

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320311412809 ◽

2011 ◽

Vol 12 (4) ◽

pp. 456-461 ◽

Cited By ~ 20

Author(s):

Masanobu Yamazato ◽

Anderson J Ferreira ◽

Yoriko Yamazato ◽

Carlos Diez-Freire ◽

Lihui Yuan ◽

...

Keyword(s):

Heart Rate ◽

Gene Transfer ◽

Angiotensin Converting Enzyme ◽

Spontaneously Hypertensive Rats ◽

Nucleus Tractus Solitarius ◽

Converting Enzyme ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Angiotensin Converting Enzyme 2 ◽

Ace2 Gene

The renin–angiotensin system (RAS) in the nucleus tractus solitarius (NTS) is an important modulator of the baroreceptor heart rate reflex. This study tested the hypothesis that angiotensin-converting enzyme 2 (ACE2) expression is decreased in the NTS of spontaneously hypertensive rats (SHRs) and that its gene transfer in this nucleus would lead to beneficial effects on baroreflex function since this enzyme is key in the regulation of the vasoprotective axis of the RAS. ACE2 protein levels and its activity were significantly decreased in the NTS of SHRs compared to normotensive Wistar-Kyoto (WKY) control rats. Rats instrumented with radio-telemetry transducers received NTS microinjection of either Lenti-ACE2 (Lentiviral vector-mediated gene transfer of ACE2) or lenti-GFP (green fluorescent protein). The ACE2 gene transfer into the NTS resulted in long-term overexpression of ACE2. This was associated with a 60% increase in heart rate baroreflex sensitivity in the lenti-ACE2 injected SHRs compared with the lenti-GFP injected control SHRs (0.27 ± 0.02 ms/mmHg in lenti-GFP rats vs. 0.44 ± 0.07 ms/mmHg in lenti-ACE2 rats). These observations demonstrate that ACE2 gene transfer overcomes its intrinsic decrease in the NTS of SHRs and improves baroreceptor heart rate reflex.

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Angiotensin-converting enzyme 2 (ACE2) is upregulated in Alzheimer’s disease brain

10.1101/2020.10.08.331157 ◽

2020 ◽

Cited By ~ 2

Author(s):

Qiyue Ding ◽

Nataliia V. Shults ◽

Brent T. Harris ◽

Yuichiro J. Suzuki

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Angiotensin Converting Enzyme ◽

Protein Expression ◽

Neurodegenerative Disorder ◽

Host Cells ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

The Brain

AbstractAlzheimer’s disease is a chronic neurodegenerative disorder and represents the main cause of dementia. Currently, the world is suffering from the pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur. The present study demonstrates that the protein expression level of ACE2 is upregulated in the brain of Alzheimer’s disease patients. The increased ACE2 expression is not age-dependent, suggesting the direct relationship between Alzheimer’s disease and the ACE2 expression. Oxidative stress has been implicated in the pathogenesis of Alzheimer’s disease, and Alzheimer’s disease brains examined in this study also exhibited higher carbonylated proteins as well as increased thiol oxidation state of peroxiredoxin 6 (Prx6). The positive correlation was found between the increased ACE2 protein expression and oxidative stress in Alzheimer’s disease brain. Thus, the present study reveals the relationships between Alzheimer’s disease and ACE2, the receptor for SARS-CoV-2. These results warrant monitoring Alzheimer’s disease patients with COVID-19 carefully for the possible higher viral load in the brain and long-term adverse neurological consequences.

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Abstract MP086: Association Between the Angiotensin-Converting Enzyme-2 Gene and Blood Pressure in a Cohort of Canadian Adolescents

Circulation ◽

10.1161/circ.125.suppl_10.amp086 ◽

2012 ◽

Vol 125 (suppl_10) ◽

Author(s):

Lucile Malard ◽

Lisa Kakinami ◽

Jennifer O’Loughlin ◽

Marie-Hélène Roy-Gagnon ◽

Aurélie Labbe ◽

...

Keyword(s):

Blood Pressure ◽

Linkage Disequilibrium ◽

Angiotensin Converting Enzyme ◽

Growth Models ◽

Nucleotide Polymorphisms ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Link Type ◽

Oscillometric Device ◽

Ace2 Gene

Background: The Angiotensin-Converting Enzyme-2 (ACE2) gene, located on chromosome X, is believed to be implicated in blood pressure (BP) regulation. However the few studies that have assessed this association have yielded mixed results. We examined the association between BP and ACE2 single nucleotide polymorphisms (SNPs) in a population-based cohort of adolescents, thereby minimizing confounding by treatment for hypertension and other chronic diseases. Methods: Participants were 852 of 1293 adolescents from the Nicotine Dependence In Teens (NDIT) cohort study. Participants provided a blood sample for DNA, and BP was measured on the right arm at rest, in the sitting position, by trained, certified technicians using an automated oscillometric device at age 12, 15 and 17 years. Instruments were calibrated against mercury sphygmomanometer before each data collection. Systolic (SBP) and diastolic blood pressure (DBP) were measured 3 times at 1-minute intervals, and the mean was used for analysis. Four SNPs (rs2074192, rs233575 , rs2158083, rs1978124) in the ACE2 gene were genotyped. The relationship between ACE2 SNPs and each of SBP and DBP was examined using linear growth models adjusted for height and ethnicity, and stratified by sex. Results: Mean age at baseline was 12.7 years; 47.8% of participants were male (n=407 of 852). All SNPs were in Hardy-Weinberg equilibrium (p>0.05), and three of the four SNPs were in linkage disequilibrium ( rs233575 and rs2158083 r2: 0.71; rs1978124 and rs233575 r2: 0.36; rs2158083 and rs1978124 r2: 0.52) with each other. SNP rs2074192 was in low linkage disequilibrium with these 3 SNPs (r2 <0.3). Compared to boys carrying the G allele, SBP in boys carrying the A allele of SNP rs2074192 was 2.45 mmHg lower (CI: 0.20-4.70, p=0.0350); DBP was 1.67 mmHg lower (CI: 0.47-2.87, p=0.0067). SNPs rs233575 , rs2158083, and rs1978124 were not significantly associated with SBP or DBP in boys. None of the four SNPs were associated with SBP or DBP in girls. Conclusion: Because elevated BP tracks from childhood to adulthood, the ACE2 gene could represent a new therapeutic target in boys to prevent elevated BP. Association between this gene and BP and potential for prevention should be further investigated.

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Angiotensin-converting enzyme 2 regulates renal atrial natriuretic peptide through angiotensin-(1–7)

Clinical Science ◽

10.1042/cs20110403 ◽

2012 ◽

Vol 123 (1) ◽

pp. 29-37 ◽

Cited By ~ 19

Author(s):

Stella Bernardi ◽

Wendy C. Burns ◽

Barbara Toffoli ◽

Raelene Pickering ◽

Maryio Sakoda ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Kidney Diseases ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Renal Tubular Cells ◽

Gene And Protein Expression ◽

Glomerular Lesions ◽

Atrial Natriuretic

Deficiency of ACE2 (angiotensin-converting enzyme 2), which degrades Ang (angiotensin) II, promotes the development of glomerular lesions. However, the mechanisms explaining why the reduction in ACE2 is associated with the development of glomerular lesions have still to be fully clarified. We hypothesized that ACE2 may regulate the renoprotective actions of ANP (atrial natriuretic peptide). The aim of the present study was to investigate the effect of ACE2 deficiency on the renal production of ANP. We evaluated molecular and structural abnormalities, as well as the expression of ANP in the kidneys of ACE2-deficient mice and C57BL/6 mice. We also exposed renal tubular cells to AngII and Ang-(1–7) in the presence and absence of inhibitors and agonists of RAS (renin–angiotensin system) signalling. ACE2 deficiency resulted in increased oxidative stress, as well as pro-inflammatory and profibrotic changes. This was associated with a down-regulation of the gene and protein expression on the renal production of ANP. Consistent with a role for the ACE2 pathway in modulating ANP, exposing cells to either Ang-(1–7) or ACE2 or the Mas receptor agonist up-regulated ANP gene expression. This work demonstrates that ACE2 regulates renal ANP via the generation of Ang-(1–7). This is a new mechanism whereby ACE2 counterbalances the renal effects of AngII and which explains why targeting ACE2 may be a promising strategy against kidney diseases, including diabetic nephropathy.

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Anatomical and timely assessment of protein expression of angiotensin‐converting enzyme 2, SARS‐CoV ‐2 specific receptor, in fetal and placental tissues: new insight for perinatal counseling

Ultrasound in Obstetrics and Gynecology ◽

10.1002/uog.22178 ◽

2020 ◽

Author(s):

V. Faure‐Bardon ◽

P. Isnard ◽

N. Roux ◽

M. Leruez‐Ville ◽

T. Molina ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Protein Expression ◽

Converting Enzyme ◽

Specific Receptor ◽

Angiotensin Converting Enzyme 2

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Protein Expression of Angiotensin-Converting Enzyme 2 (ACE2) is Upregulated in Brains with Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22041687 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1687

Author(s):

Qiyue Ding ◽

Nataliia V. Shults ◽

Sergiy G. Gychka ◽

Brent T. Harris ◽

Yuichiro J. Suzuki

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Angiotensin Converting Enzyme ◽

Protein Expression ◽

Neurodegenerative Disorder ◽

Host Cells ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

The Brain

Alzheimer’s disease is a chronic neurodegenerative disorder and represents the main cause of dementia globally. Currently, the world is suffering from the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur. The present study demonstrates that the protein expression level of ACE2 is upregulated in the brain of patients with Alzheimer’s disease. The increased ACE2 expression is not age-dependent, suggesting the direct relationship between Alzheimer’s disease and ACE2 expression. Oxidative stress has been implicated in the pathogenesis of Alzheimer’s disease, and brains with the disease examined in this study also exhibited higher carbonylated proteins, as well as an increased thiol oxidation state of peroxiredoxin 6 (Prx6). A moderate positive correlation was found between the increased ACE2 protein expression and oxidative stress in brains with Alzheimer’s disease. In summary, the present study reveals the relationships between Alzheimer’s disease and ACE2, the receptor for SARS-CoV-2. These results suggest the importance of carefully monitoring patients with both Alzheimer’s disease and COVID-19 in order to identify higher viral loads in the brain and long-term adverse neurological consequences.

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