Diminazene aceturate prevents nephropathy by increasing glomerular ACE2 and AT<sub>2</sub> receptor expression in a rat model of type1 diabetes

Goru, Santosh Kumar; Kadakol, Almesh; Malek, Vajir; Pandey, Anuradha; Sharma, Nisha; Gaikwad, Anil Bhanudas

doi:10.1111/bph.13946

Cited by 64 publications

(54 citation statements)

References 54 publications

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“…All other mice received equivalent volumes of vehicle (saline) injections. This dose was based on several previous studies showing that the optimal dose of DIZE in inducing ACE2 activity was 15 mg/kg/ day [39,43,44] and a preliminary study of our own across a range of DIZE concentrations by IP that confirmed previous findings (data not shown).…”

Section: Drugssupporting

confidence: 69%

ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease

et al. 2020

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Mid-life hypertension and cerebrovascular dysfunction are associated with increased risk of later life dementia, including Alzheimer's disease (AD). The classical renin-angiotensin system (cRAS), a physiological regulator of blood pressure, functions independently within the brain and is overactive in AD. cRAS-targeting anti-hypertensive drugs are associated with reduced incidence of AD, delayed onset of cognitive decline, and reduced levels of Aβ and tau in both animal models and human pathological studies. cRAS activity is moderated by a downstream regulatory RAS pathway (rRAS), which is underactive in AD and is strongly associated with pathological hallmarks in human AD, and cognitive decline in animal models of CNS disease. We now show that enhancement of brain ACE2 activity, a major effector of rRAS, by intraperitoneal administration of diminazene aceturate (DIZE), an established activator of ACE2, lowered hippocampal Aβ and restored cognition in mid-aged (13-14-month-old) symptomatic Tg2576 mice. We confirmed that the protective effects of DIZE were directly mediated through ACE2 and were associated with reduced hippocampal soluble Aβ 42 and IL1-β levels. DIZE restored hippocampal MasR levels in conjunction with increased NMDA NR2B and downstream ERK signalling expression in hippocampal synaptosomes from Tg2576 mice. Chronic (10 weeks) administration of DIZE to pre-symptomatic 9-10-month-old Tg2576 mice, and acute (10 days) treatment in cognitively impaired 12-13-month-old mice, prevented the development of cognitive impairment. Together these data demonstrate that ACE2 enhancement protects against and reverses amyloid-related hippocampal pathology and cognitive impairment in a preclinical model of AD.

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Section: Drugssupporting

confidence: 69%

ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease

et al. 2020

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“…Wild-type mice were randomly divided into five groups (n = 10 each) as follows: 1) wild-type control group, 2) wild-type silicosis model group, 3) DIZE (15 mg/kg/day, i. p., D7770; Sigma-Aldrich, St. Louis, MO, USA) 15 treatment group, 4) DIZE + A779 (5 mg/kg/day, s.c., 4030357; Bachem, Bubendorf, Switzerland) 16 treatment group, and 5) DIZE + MLN-4760 (1 mg/kg/day, s.c. 530,616; Millipore, Darmstadt, Germany) 17 treatment group. The hACE2-transgenic ICR mice were randomly divided into four groups (n = 10 each) as follows: 1) hACE2-transgenic control group; 2) hACE2-transgenic silicosis model group, 3) A779 treatment group, and 4) MLN-4760 treatment group.…”

Section: Animals and Experimental Proceduresmentioning

confidence: 99%

<p>ACE2 Attenuates Epithelial-Mesenchymal Transition in MLE-12 Cells Induced by Silica</p>

et al. 2020

DDDT

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The role of angiotensin-converting enzyme 2 (ACE2) in silicosis remains unknown, although previous studies have suggested that ACE2 may be beneficial. We, therefore, investigated the effect of ACE2 on silicosis, particularly with regard to its role in regulating the epithelial-mesenchymal transition (EMT) induced by silica, with the aim to uncover a new potential target for the treatment of pulmonary fibrosis. Materials and Methods: We employed wild-type mice treated with diminazene aceturate (DIZE, an ACE2 activator, 15 mg/kg/day for 4 weeks), hACE2-transgenic mice (overexpress the ACE2 gene), and the mouse lung type II epithelial cell line treated with DIZE (10 −7 M for 48 h) or angiotensin-(1-7) [Ang-(1-7)] (10 −4 M for 48 h), following induced fibrotic responses to determine the protective potential of ACE2. Silicosis models were established by orotracheal instillation of SiO 2 (2.5 mg/mouse). Immunostaining was used to determine αsmooth muscle actin (α-SMA) expression. The activities of angiotensin-converting enzyme (ACE) and ACE2 and the levels of angiotensin II (Ang II) and Ang-(1-7) were detected by enzyme-linked immunosorbent assay. The mRNA expression of ACE and ACE2, and protein expression of the renin-angiotensin system (RAS) components and EMT indicators were studied by qRT-PCR and Western blot, respectively. Results: DIZE treatment and overexpression of ACE2 markedly inhibited the formation of silica-induced lung fibrosis and increased the level of E-cadherin, with concomitant downregulation of pro-collagen, vimentin, and α-SMA via RAS signaling. Furthermore, DIZE and Ang-(1-7) attenuated the EMT and collagen deposition induced by silica in MLE-12 cells. Moreover, these effects were abrogated by MLN-4760 (a specific ACE2 inhibitor) and A779 (a specific Mas receptor blocker). Conclusion: The overexpression of ACE2 and treatment with DIZE can ameliorate EMT in silicotic mice via activation of the ACE2-Ang-(1-7)-Mas receptor axis, and these changes are accompanied by suppression of the ACE-Ang II-AT1 receptor axis.

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“…Interestingly, diabetic rats using streptozotocin, treatment with DIZE restored ACE2 expression in isolated glomeruli and this was associated with increased expression of AT2R . DIZE reduced AngII levels in the whole kidney of diabetic rats and augmented Ang (1‐7) expression . The AT2R antagonist, PD123319 reversed the effect of DIZE, suggesting that DIZE protects the kidney via the ACE2/Ang (1‐7)/AT2 pathway …”

Section: The Potential Role Of Dize In Treating Vascular/endothelial mentioning

confidence: 98%

“…46 Interestingly, diabetic rats using streptozotocin, treatment with DIZE restored ACE2 expression in isolated glomeruli and this was associated with increased expression of AT2R. 49…”

Section: Dize In Cardiac and Renal Tissuementioning

confidence: 98%

“…In addition, in the renal cortex of rats with kidney disease, subcutaneous injection of DIZE (15 mg/kg/d for 2 weeks) is associated with a reduction of cortical ACE activity and an increase in cortical ACE2 activity . Interestingly, diabetic rats using streptozotocin, treatment with DIZE restored ACE2 expression in isolated glomeruli and this was associated with increased expression of AT2R . DIZE reduced AngII levels in the whole kidney of diabetic rats and augmented Ang (1‐7) expression .…”

Section: The Potential Role Of Dize In Treating Vascular/endothelial mentioning

confidence: 99%

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The potential actions of angiotensin‐converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases

Qaradakhi

Gadanec

McSweeney

et al. 2020

Clin Exp Pharma Physio

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The renin angiotensin system (RAS) regulates fluid balance, blood pressure and maintains vascular tone. The potent vasoconstrictor angiotensin II (Ang II) produced by angiotensin‐converting enzyme (ACE) comprises the classical RAS. The non‐classical RAS involves the conversion of Ang II via ACE2 into the vasodilator Ang (1‐7) to counterbalance the effects of Ang II. Furthermore, ACE2 converts AngA into another vasodilator named alamandine. The over activation of the classical RAS (increased vasoconstriction) and depletion of the non‐classical RAS (decreased vasodilation) results in vascular dysfunction. Vascular dysfunction is the leading cause of atherosclerosis and cardiovascular disease (CVD). Additionally, local RAS is expressed in various tissues and regulates cellular functions. RAS dysregulation is involved in other several diseases such as inflammation, renal dysfunction and even cancer growth. An approach in restoring vascular dysfunction and other pathological diseases is to either increase the activity of ACE2 or reduce the effect of the classical RAS by counterbalancing Ang II effects. The antitrypanosomal agent, diminazene aceturate (DIZE), is one approach in activating ACE2. DIZE has been shown to exert beneficial effects in CVD experimental models of hypertension, myocardial infarction, type 1 diabetes and atherosclerosis. Thus, this review focuses on DIZE and its effect in several tissues such as blood vessels, cardiac, renal, immune and cancer cells.

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Diminazene aceturate prevents nephropathy by increasing glomerular ACE2 and AT₂ receptor expression in a rat model of type1 diabetes

Cited by 64 publications

References 54 publications

ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease

ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease

<p>ACE2 Attenuates Epithelial-Mesenchymal Transition in MLE-12 Cells Induced by Silica</p>

The potential actions of angiotensin‐converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases

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Diminazene aceturate prevents nephropathy by increasing glomerular ACE2 and AT2 receptor expression in a rat model of type1 diabetes

Cited by 64 publications

References 54 publications

ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease

ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease

<p>ACE2 Attenuates Epithelial-Mesenchymal Transition in MLE-12 Cells Induced by Silica</p>

The potential actions of angiotensin‐converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases

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Diminazene aceturate prevents nephropathy by increasing glomerular ACE2 and AT₂ receptor expression in a rat model of type1 diabetes