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results
Hyperglycemia, hydroxychloroquine, and the COVID-19 pandemic.
J Med Virol. 2020 Apr 15. doi: 10.1002/jmv.25887. Online ahead of print.
PMID: 32293710
Review.
Coronavirus disease-2019 (COVID-19) infection and its severity can be
explained by the concentration of glycosylated severe acute respiratory
syndrome-coronavirus 2 (SARS-CoV-2) viral particles in the lung
epithelium, the concentration of glycosylated angiotensin-converting
enzyme receptor 2 (ACE2) in the lung epithelium, and the degree and
control of the pulmonary immune response to the SARS-CoV-2 spike protein
at approximately day 8 to 10 after symptom onset, which may be related
to both. Binding of ACE2 by SARS-CoV-2 in COVID-19 also suggests that
prolonged uncontrolled hyperglycemia, and not just a history of diabetes
mellitus, may be important in the pathogenesis of the disease. It is
tempting to consider that the same mechanism acts in COVID-19 as in
SARS, where an overactive macrophage M1 inflammatory response, as
neutralizing antibodies to the SARS-CoV-2 spike protein form at day 7 to
10, results in acute respiratory distress syndrome (ARDS) in
susceptible patients. It also allows consideration of agents, such as
hydroxychloroquine, which may interfere with this overly brisk
macrophage inflammatory response and perhaps influence the course of the
disease, in particular, those that blunt but do not completely abrogate
the M1 to M2 balance in macrophage polarization, as well as viral load,
which in SARS appears to be temporally related to the onset of ARDS.
2.
ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity.
Diabetes. 2016 Jan;65(1):85-95. doi: 10.2337/db15-0399. Epub 2015 Jul 29.
PMID: 26224885
Free PMC article.
Obesity is increasing in prevalence and is strongly associated
with metabolic and cardiovascular disorders. The renin-angiotensin
system (RAS) has emerged as a key pathogenic mechanism for these
disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively
regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role
of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and
wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and
studied at 6 months of age. Loss of ACE2 resulted in decreased weight
gain but increased glucose intolerance, epicardial adipose tissue (EAT)
inflammation, and polarization of macrophages into a proinflammatory
phenotype in response to HFD. Similarly, human EAT in patients with
obesity and heart failure displayed a proinflammatory macrophage
phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was
associated with decreased myocardial adiponectin, decreased
phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity,
and myocardial insulin resistance, which worsened heart function. Ang
1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated
EAT inflammation and reduced cardiac steatosis and lipotoxicity,
resulting in normalization of heart failure. In conclusion, ACE2 plays a
novel role in heart disease associated with obesity wherein ACE2
negatively regulates obesity-induced EAT inflammation and cardiac
insulin resistance.
© 2016 by the American Diabetes Association. Readers may use this
article as long as the work is properly cited, the use is educational
and not for profit, and the work is not altered.
3.
Activation of ACE2/angiotensin (1-7) attenuates pancreatic β cell dedifferentiation in a high-fat-diet mouse model.
Metabolism. 2018 Apr;81:83-96. doi: 10.1016/j.metabol.2017.12.003. Epub 2017 Dec 7.
PMID: 29225087
OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2) has been identified in pancreatic islets and can preserve β cells. In this study, we aimed to examine the possible role of ACE2 and its end product, angiotensin 1-7 (A1-7), in reducing β cell dedifferentiation during …
ACE2 deficiency reduces β-cell mass and impairs β-cell proliferation in obese C57BL/6 mice.
Am J Physiol Endocrinol Metab. 2015 Oct 1;309(7):E621-31. doi: 10.1152/ajpendo.00054.2015. Epub 2015 Aug 4.
PMID: 26389599
Free PMC article.
Drugs that inhibit the renin-angiotensin system (RAS) decrease the onset
of type 2 diabetes (T2D). Pancreatic islets express RAS components,
including angiotensin-converting enzyme 2 (ACE2), which cleaves
angiotensin II (Ang II) to angiotensin-(1-7) [Ang-(1-7)]. Overexpression
of ACE2 in pancreas of diabetic mice improved glucose homeostasis. The
purpose of this study was to determine if deficiency of endogenous ACE2
contributes to islet dysfunction and T2D. We hypothesized that ACE2
deficiency potentiates the decline in β-cell function and augments the
development of diet-induced T2D. Male Ace2(+/y) or Ace2(-/y) mice were
fed a low-fat (LF) or high-fat (HF) diet for 1 or 4 mo. A subset of 1-mo
HF-fed mice were infused with Sal (Sal), losartan (Los), or Ang-(1-7).
At 4 mo, while both genotypes of HF-fed mice developed a similar level
of insulin resistance, adaptive hyperinsulinemia was reduced in
Ace2(-/y) vs. Ace2(+/y) mice. Similarly, in vivo glucose-stimulated
insulin secretion (GSIS) was reduced in 1-mo HF-fed Ace2(-/y) compared
with Ace2(+/y) mice, resulting in augmented hyperglycemia. The average
islet area was significantly smaller in both LF- and HF-fed Ace2(-/y)
vs. Ace2(+/y) mice. Additionally, β-cell mass and proliferation were
reduced significantly in HF-fed Ace2(-/y) vs. Ace2(+/y) mice. Neither
infusion of Los nor Ang-(1-7) was able to correct impaired in vivo GSIS
of HF-fed ACE2-deficient mice. These results demonstrate a critical role
for endogenous ACE2 in the adaptive β-cell hyperinsulinemic response to
HF feeding through regulation of β-cell proliferation and growth.
5.
Nrf2 Deficiency Upregulates Intrarenal
Angiotensin-Converting Enzyme-2 and Angiotensin 1-7 Receptor Expression
and Attenuates Hypertension and Nephropathy in Diabetic Mice.
Endocrinology. 2018 Feb 1;159(2):836-852. doi: 10.1210/en.2017-00752.
PMID: 29211853
Free PMC article.
We investigated the role of nuclear factor erythroid 2-related factor 2
(Nrf2) in renin-angiotensin system (RAS) gene expression in renal
proximal tubule cells (RPTCs) and in the development of systemic
hypertension and kidney injury in diabetic Akita mice. We used adult
male Akita Nrf2 knockout mice and Akita mice treated with trigonelline
(an Nrf2 inhibitor) or oltipraz (an Nrf2 activator). We also examined
rat immortalized RPTCs (IRPTCs) stably transfected with control plasmids
or plasmids containing rat angiotensinogen (Agt),
angiotensin-converting enzyme (ACE), angiotensin-converting enzyme-2
(Ace2), or angiotensin 1-7 (Ang 1-7) receptor (MasR) gene promoters.
Genetic deletion of Nrf2 or pharmacological inhibition of Nrf2 in Akita
mice attenuated hypertension, renal injury, tubulointerstitial fibrosis,
and the urinary albumin/creatinine ratio. Furthermore, loss of Nrf2
upregulated RPTC Ace2 and MasR expression, increased urinary Ang 1-7
levels, and downregulated expression of Agt, ACE, and profibrotic genes
in Akita mice. In cultured IRPTCs, Nrf2 small interfering RNA
transfection or trigonelline treatment prevented high glucose
stimulation of Nrf2 nuclear translocation, Agt, and ACE transcription
with augmentation of Ace2 and MasR transcription, which was reversed by
oltipraz. These data identify a mechanism, Nrf2-mediated stimulation of
intrarenal RAS gene expression, by which chronic hyperglycemia induces
hypertension and renal injury in diabetes.
Urinary ACE2 in healthy adults and patients with uncomplicated type 1 diabetes.
7.
Can J Physiol Pharmacol. 2014 Aug;92(8):703-6. doi: 10.1139/cjpp-2014-0065. Epub 2014 May 15.
PMID: 24920267
Angiotensin-converting enzyme 2 (ACE2) is expressed in the kidney
and may be renoprotective. We determined whether urinary ACE2 enzyme
activity and protein levels (ELISA), as well as angiotensinogen and ACE,
are elevated during clamped euglycemia (4-6 mmol·L(-1)) in patients
with uncomplicated type 1 diabetes (T1D, n = 58) compared with
normoglycemic controls (n = 21). We also measured the effect of clamped
hyperglycemia (9-11 mmol·L(-1)) on each urinary factor in T1D patients.
Urinary ACE2 activity and protein levels were higher during clamped
euglycemia in T1D compared with the controls (p < 0.0001). In
contrast, urinary angiotensinogen (AGT) levels (p = 0.27) and ACE excretion (p
= 0.68) did not differ. In response to clamped hyperglycemia in T1D,
urinary ACE2 protein decreased (p < 0.0001), whereas urinary ACE2
activity as well as angiotensinogen and ACE levels remained unchanged.
Urinary ACE2 activity and protein expression are increased in T1D
patients prior to the onset of clinical complications. Further work is
required to determine the functional role of urinary ACE2 in early T1D.
Keywords:
ECA2 urinaire; diabetes mellitus; diabète sucré; urinary ACE2. 7.
Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice.
Am J Physiol Renal Physiol. 2014 Mar 15;306(6):F629-39. doi: 10.1152/ajprenal.00516.2013. Epub 2014 Jan 22.
PMID: 24452639
Free PMC article.
Abstract
Angiotensin-converting enzyme 2 (ACE2) is located in several
tissues and is highly expressed in renal proximal tubules, where it
degrades the vasoconstrictor angiotensin II (ANG II) to ANG-(1-7).
Accumulating evidence supports protective roles of ACE2 in several
disease states, including diabetic nephropathy. A disintegrin and
metalloprotease (ADAM) 17 is involved in the shedding of several
transmembrane proteins, including ACE2. Our previous studies showed
increased renal ACE2, ADAM17 expression, and urinary ACE2 in type 2
diabetic mice (Chodavarapu H, Grobe N, Somineni HK, Salem ES, Madhu M,
Elased KM. PLoS One 8: e62833, 2013). The aim of the present study was
to determine the effect of insulin on ACE2 shedding and ADAM17 in type 1
diabetic Akita mice. Results demonstrate increased renal ACE2 and
ADAM17 expression and increased urinary ACE2 fragments (≈70 kDa) and
albumin excretion in diabetic Akita mice. Immunostaining revealed
colocalization of ACE2 with ADAM17 in renal tubules. Renal proximal
tubular cells treated with ADAM17 inhibitor showed reduced ACE2 shedding
into the media, confirming ADAM17-mediated shedding of ACE2. Treatment
of Akita mice with insulin implants for 20 wk normalized hyperglycemia
and decreased urinary ACE2 and albumin excretion. Insulin also
normalized renal ACE2 and ADAM17 but had no effect on tissue inhibitor
of metalloproteinase 3 (TIMP3) protein expression. There was a positive
linear correlation between urinary ACE2 and albuminuria, blood glucose,
plasma creatinine, glucagon, and triglycerides. This is the first report
showing an association between hyperglycemia, cardiovascular risk
factors, and increased shedding of urinary ACE2 in diabetic Akita mice.
Urinary ACE2 could be used as a biomarker for diabetic nephropathy and
as an index of intrarenal ACE2 status.
8.
8.
High urinary ACE2 concentrations are associated with severity of glucose intolerance and microalbuminuria.
Eur J Endocrinol. 2013 Jan 17;168(2):203-10. doi: 10.1530/EJE-12-0782. Print 2013 Feb.
PMID: 23144053
OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2) plays an important role in glucose metabolism and renal function. However, the relationship between ACE2 and hyperglycemia or microalbuminuria has not been established in humans. We investigated whether urinar …
Daily exercise training protects against albuminuria and
angiotensin converting enzyme 2 shedding in db/db diabetic mice.
J Endocrinol. 2014 Apr 22;221(2):235-51. doi: 10.1530/JOE-13-0532. Print 2014 May.
PMID: 24756098
Free PMC article.Angiotensin II (Ang II) is involved in induction and progression of
renal damage in diabetes. Angiotensin converting enzyme 2 (ACE2) is
highly expressed in the kidney and has been shown to be renoprotective
by degrading Ang II to Ang-(1-7). A disintegrin and metalloproteinase 17
(ADAM17)-mediated shedding of renal ACE2 contribute to diabetic
nephropathy pathogenesis. Lifestyle modification and metformin are
recommended as initial therapies for most patients with type 2 diabetes.
The aim of this study was to investigate whether exercise training
and/or metformin improve glucose homeostasis and albuminuria and
downregulate renal ADAM17 and ACE2 shedding in db/db mice.
Seven-week-old normal and db/db mice were subjected either to a
sedentary existence or exercise training with and without metformin (150
mg/kg per day) for 10 weeks. Exercise training significantly lowered
blood glucose, urinary albumin and ACE2 excretion in db/db mice. ADAM17
and ACE2 proteins were co-localized in cortical tubules of the kidney,
indicating a possible interaction. Metformin treatment was effective in
lowering hyperglycemia only during the first 2 weeks of treatment.
Increased renal ADAM17 in 17-week-old db/db mice was corrected by
physical exercise but not metformin. In addition, exercise training
reduced plasma triglycerides and enhanced insulin levels of db/db mice.
In conclusion, exercise training alone and in combination with metformin
prevented shedding of renal ACE2 by decreasing ADAM17 protein. Urinary
ACE2 could serve as a prognostic tool for the progression of kidney
damage and its attenuation by exercise may partially contribute to its
renal protection.
Angiotensin II type 2 receptor and
angiotensin-converting enzyme 2 mediate ischemic renal injury in
diabetic and non-diabetic rats.
Life Sci. 2019 Oct 15;235:116796. doi: 10.1016/j.lfs.2019.116796. Epub 2019 Aug 27.
PMID: 31470003
However, same is still elusive under AKI and hyperglycaemia
comorbidity. Hence, the present study delineates the role of
angiotensin-II type 2 receptor (AT2R) and angiotensin-converting enzyme 2
(ACE2) in AKI under normal and hyperglycaemia condition. ...Co-a …
Conclusion:
We demonstrated that pharmacological activation of AT2R and ACE2
protects DM and ND rats from IRI by preventing oxidative stress,
inflammation and apoptosis-mediated tubular damage.
Keywords: ACE2 activator; AT2R agonist; Diabetes; Ischemic renal injury; Renin-angiotensin system.
Keywords: ACE2 activator; AT2R agonist; Diabetes; Ischemic renal injury; Renin-angiotensin system.
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