Vasoconstrictor Effects of Trace Amine-Associated Receptor Agonists in the Isolated Perfused Rat Kidney.

Introduction: Endogenous trace amines such as tryptamine and 3-iodothyronamine (T1AM) are present in mammalian tissues at very low concentrations. They produce their actions by activating surface G protein-coupled receptors known as trace amine-associated receptors (TAARs).

Objective: The study was designed to investigate the possible vasoconstrictor effects of tryptamine, T1AM, and the selective TAAR1 agonist RO5263397 in isolated perfused rat kidney.

Vasodilator Effect of Trace Amines, 3-Iodothyronamine, and RO5263397 in the Rat Perfused Kidney: Comparison with Tryptamine.

Introduction: Trace amine-associated receptors (TAARs) are a family of G protein-coupled receptors and are widely distributed in the body. Activation of TAAR1 by specific agonists can produce a variety of physiological effects centrally and peripherally. The objective of this study was to investigate the vasodilator effect of two selective TAAR1 agonists 3-iodothyronamine (T1AM) and RO5263397 in the isolated perfused rat kidney preparation.

Hydrogen sulfide donor GYY4137 attenuates vascular complications in mesenteric bed of streptozotocin-induced diabetic rats.

Unlabelled: Hydrogen sulfide (HS) has been reported to have beneficial effects in different pathological conditions.

Objectives: the effects of chronic treatment of diabetic rats with GYY4137 (slow releasing HS donor) or NaHS (fast releasing HS donor) on the reactivity of the mesenteric bed to vasoactive agonists and the changes in its downstream effectors, ERK1/2 and p38 MAP Kinase have been investigated. In addition, the levels of nitric oxide (NO) and HS in all groups were measured.

Chronic Treatment With Hydrogen Sulfide Donor GYY4137 Mitigates Microglial and Astrocyte Activation in the Spinal Cord of Streptozotocin-Induced Diabetic Rats.

Long-term diabetic patients suffer immensely from diabetic neuropathy. This study was designed to investigate the effects of hydrogen sulfide (H2S) on peripheral neuropathy, activation of microglia, astrocytes, and the cascade secretion of proinflammatory cytokines in the streptozotocin (STZ)-induced peripheral diabetic neuropathy rat model. STZ-induced diabetic rats were treated with the water-soluble, slow-releasing H2S donor GYY4137 (50 mg/kg; i.

Alleviation of impaired reactivity in the corpus cavernosum of STZ-diabetic rats by slow-release HS donor GYY4137.

GYY4137 is a novel hydrogen sulfide (HS) releasing molecule with vasodilator activity. The objectives of this study were to investigate: (1) the pharmacological effect of GYY4137 on the reactivity of the corpus cavernosum (CC) from normal and diabetic rats; (2) the contribution of ATP-sensitive potassium (K-ATP) channels and nitric oxide (NO) pathway; (3) the reactivity to vasoactive agonists following ex vivo incubation of the diabetic rat CC with GYY4137. Longitudinal strips of CC from control and diabetic male Sprague-Dawley (SD) rats (n = 5-6 animals per group) were suspended in organ-baths.

Angiotensin-(1-7)-dependent vasorelaxation of the renal artery exhibits unique angiotensin and bradykinin receptor selectivity.

Angiotensin-(1-7) [Ang-(1-7)] exhibits blood pressure lowering actions, inhibits cell growth, and reduces tissue inflammation and fibrosis which may functionally antagonize an activated Ang II-AT receptor axis. Since the vascular actions of Ang-(1-7) and the associated receptor/signaling pathways vary in different vascular beds, the current study established the vasorelaxant properties of the heptapeptide in the renal artery of male Wistar male rats. Ang-(1-7) produced an endothelium-dependent vasodilator relaxation of isolated renal artery segments pre-contracted by a sub-maximal concentration of phenylephrine (PE) (3×10M).

Transactivation of ErbB Family of Receptor Tyrosine Kinases Is Inhibited by Angiotensin-(1-7) via Its Mas Receptor.

Transactivation of the epidermal growth factor receptor (EGFR or ErbB) family members, namely EGFR and ErbB2, appears important in the development of diabetes-induced vascular dysfunction. Angiotensin-(1-7) [Ang-(1-7)] can prevent the development of hyperglycemia-induced vascular complications partly through inhibiting EGFR transactivation. Here, we investigated whether Ang-(1-7) can inhibit transactivation of ErbB2 as well as other ErbB receptors in vivo and in vitro.

Cationic Polyamidoamine Dendrimers as Modulators of EGFR Signaling In Vitro and In Vivo.

Cationic polyamidoamine (PAMAM) dendrimers are branch-like spherical polymers being investigated for a variety of applications in nanomedicine including nucleic acid drug delivery. Emerging evidence suggests they exhibit intrinsic biological and toxicological effects but little is known of their interactions with signal transduction pathways. We previously showed that the activated (fragmented) generation (G) 6 PAMAM dendrimer, Superfect (SF), stimulated epidermal growth factor receptor (EGFR) tyrosine kinase signaling-an important signaling cascade that regulates cell growth, survival and apoptosis- in cultured human embryonic kidney (HEK 293) cells.

The dual targeting of EGFR and ErbB2 with the inhibitor Lapatinib corrects high glucose-induced apoptosis and vascular dysfunction by opposing multiple diabetes-induced signaling changes.

The epidermal growth factor receptors, EGFR and EGFR2 (ErbB2), appear important mediators of diabetes-induced vascular dysfunction. We investigated whether targeted dual inhibition of EGFR and ErbB2 with Lapatinib would be effective in treating diabetes-induced vascular dysfunction in a rat model of type 1 diabetes. In streptozotocin-induced diabetes, chronic 4-week oral or acute, ex vivo, administration of Lapatinib prevented the development of vascular dysfunction as indicated by the attenuation of the hyper-reactivity of the diabetic mesenteric vascular bed (MVB) to norephinephrine without correcting hyperglycemia.

Chronic treatment with Ang-(1-7) reverses abnormal reactivity in the corpus cavernosum and normalizes diabetes-induced changes in the protein levels of ACE, ACE2, ROCK1, ROCK2 and omega-hydroxylase in a rat model of type 1 diabetes.

Angiotensin-(1-7) [Ang-(1-7)] may have beneficial effects in diabetes mellitus-induced erectile dysfunction (DMIED) but its molecular actions in the diabetic corpus cavernosum (CC) are not known. We characterized the effects of diabetes and/or chronic in vivo administration of Ang-(1-7) on vascular reactivity in the rat corpus cavernosum (CC) and on protein expression levels of potential downstream effectors of the renin-angiotensin-aldosterone system (RAAS) such as angiotensin-converting enzyme (ACE), ACE2, Rho kinases 1 and 2 (ROCK1 and ROCK2), and omega-hydroxylase, the cytochrome-P450 enzyme that metabolizes arachidonic acid to form the vasoconstrictor, 20-hydroxyeicosatetraenoic acid. Streptozotocin-treated rats were chronicically administered Ang-(1-7) with or without A779, a Mas receptor antagonist, during weeks 4 to 6 of diabetes.

Activation of ErbB2 and Downstream Signalling via Rho Kinases and ERK1/2 Contributes to Diabetes-Induced Vascular Dysfunction.

Diabetes mellitus leads to vascular complications but the underlying signalling mechanisms are not fully understood. Here, we examined the role of ErbB2 (HER2/Neu), a transmembrane receptor tyrosine kinase of the ErbB/EGFR (epidermal growth factor receptor) family, in mediating diabetes-induced vascular dysfunction in an experimental model of type 1 diabetes. Chronic treatment of streptozotocin-induced diabetic rats (1 mg/kg/alt diem) or acute, ex-vivo (10(-6), 10(-5) M) administration of AG825, a specific inhibitor of ErbB2, significantly corrected the diabetes-induced hyper-reactivity of the perfused mesenteric vascular bed (MVB) to the vasoconstrictor, norephinephrine (NE) and the attenuated responsiveness to the vasodilator, carbachol.

Role of angiotensin II and angiotensin-(1-7) in diabetes-induced oxidative DNA damage in the corpus cavernosum.

Objective: To investigate diabetes mellitus (DM)-induced oxidative DNA damage, putative involvement of angiotensin (Ang) II, and possible modulatory effects of Ang-(1-7) in rat corpus cavernosum (CC).

Design: In vivo study.

Setting: Research laboratory.

On the nanotoxicity of PAMAM dendrimers: Superfect® stimulates the EGFR-ERK1/2 signal transduction pathway via an oxidative stress-dependent mechanism in HEK 293 cells.

Polyamidoamine (PAMAM) dendrimers are cationic branch-like macromolecules that may serve as drug delivery systems for gene-based therapies such as RNA interference. For their safe use in the clinic, they should ideally only enhance drug delivery to target tissues and exhibit no adverse effects. However, little is known about their toxicological profiles in terms of their interactions with cellular signal transduction pathways such as the epidermal growth factor receptor (EGFR).

Chronic treatment with LY294002, an inhibitor of phosphatidylinositol 3-kinase, attenuates ischemia/reperfusion-induced cardiac dysfunction in normotensive and hypertensive diabetic animals.

Diabetes is associated with increased incidence of cardiovascular disease. Mechanisms that contribute to development of diabetic cardiopathy are not well understood. Phosphatidylinositol 3-kinase (PI3K) is a family of protein kinases that play an important role in regulation of cardiac function.

Activation of EGFR/ERBB2 via pathways involving ERK1/2, P38 MAPK, AKT and FOXO enhances recovery of diabetic hearts from ischemia-reperfusion injury.

This study characterized the effects of diabetes and/or ischemia on epidermal growth factor receptor, EGFR, and/or erbB2 signaling pathways on cardiac function. Isolated heart perfusion model of global ischemia was used to study the effect of chronic inhibition or acute activation of EGFR/erbB2 signaling on cardiac function in a rat model of type-1 diabetes. Induction of diabetes with streptozotocin impaired recovery of cardiac function (cardiac contractility and hemodynamics) following 40 minutes of global ischemia in isolated hearts.

Characterization of Angiotensin-(1-7) effects on the cardiovascular system in an experimental model of type-1 diabetes.

Although exogenous administration of Angiotensin-(1-7) [Ang-(1-7)] can prevent development of diabetes induced end-organ damage, little is known about the role of endogenous Ang-(1-7) in diabetes and requires further characterization. Here, we studied the effects of chronically inhibiting endogenous Ang-(1-7) formation with DX600, a selective angiotensin converting enzyme-2 (ACE2) inhibitor, on renal and cardiac NADPH oxidase (NOX) activity, vascular reactivity and cardiac function in a model of Type-1 diabetes. The contribution of endogenous Ang-(1-7) to the protective effects of Losartan and Captopril and that of prostaglandins to the cardiovascular effects of exogenous Ang-(1-7) were also examined.

Angiotensin-(1-7) inhibits epidermal growth factor receptor transactivation via a Mas receptor-dependent pathway.

Background And Purpose: The transactivation of the epidermal growth factor (EGF) receptor appears to be an important central transduction mechanism in mediating diabetes-induced vascular dysfunction. Angiotensin-(1-7) [Ang-(1-7)] via its Mas receptor can prevent the development of hyperglycaemia-induced cardiovascular complications. Here, we investigated whether Ang-(1-7) can inhibit hyperglycaemia-induced EGF receptor transactivation and its classical signalling via ERK1/2 and p38 MAPK in vivo and in vitro.

Angiotensin-(1-7) blockade attenuates captopril- or hydralazine-induced cardiovascular protection in spontaneously hypertensive rats treated with NG-nitro-L-arginine methyl ester.

We assessed the contribution of angiotensin-(1-7) [Ang-(1-7)] to captopril-induced cardiovascular protection in spontaneously hypertensive rats (SHRs) chronically treated with the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (SHR-l). NG-nitro-L-arginine methyl ester (80 mg/L) administration for 3 weeks increased mean arterial pressure (MAP) from 196 ± 6 to 229 ± 3 mm Hg (P < 0.05).

Role of 20-hydroxyeicosatetraenoic and epoxyeicosatrienoic acids in the regulation of vascular function in a model of hypertension and endothelial dysfunction.

The objective of this study was to determine if acute inhibition of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis or reduced inactivation of epoxyeicosatrienoic acids (EETs) can correct L-N(G)-nitro-arginine-methyl-ester (L-NAME)-induced abnormal vascular reactivity in the perfused mesenteric bed and the carotid artery of spontaneously hypertensive rats (SHR). Administration of L-NAME in drinking water (80 mg/l) to SHR for 3 weeks resulted in abnormal vascular reactivity to norepinephrine and carbachol in the perfused mesenteric vascular bed and carotid artery, and significantly elevated mean arterial blood pressure (244 +/- 9 mm Hg) as compared to SHR controls drinking regular water (176 +/- 3 mm Hg). In the perfused mesenteric vascular bed, the impaired vascular responsiveness to norepinephrine was corrected by acute treatment with N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine (HET0016), an inhibitor of 20-HETE formation, but not by 1-cyclohexyl-3-dodecyl urea (CDU), an inhibitor of soluble epoxide hydrolase.

Angiotensin-(1-7) prevents diabetes-induced attenuation in PPAR-gamma and catalase activities.

The mechanisms by which angiotensin-(1-7) [Ang-(1-7)] exerts its beneficial effects on end-organ damage associated with diabetes and hypertension are not well understood. The purpose of this study was A) to compare the effects of apocynin with Ang-(1-7) on renal vascular dysfunction and NADPH oxidase activity in a combined model of diabetes and hypertension and B) to further determine whether chronic treatment with Ang-(1-7) can modulate renal catalase, and peroxisome proliferator activated receptor- gamma (PPAR-gamma) levels in streptozotocin-induced diabetes in both normotensive Wistar Kyoto rats (WKY) and in spontaneously hypertensive rats (SHR). Apocynin or Ang-(1-7) treatment for one month starting at the onset of diabetes similarly attenuated elevation of renal NADPH oxidase activity in the diabetic SHR kidney and reduced the degree of proteinuria and hyperglycemia, but had little or modest effect on reducing mean arterial pressure.

FPTIII mitigates peroxisome-mediated oxidative stress in kidneys of spontaneously hypertensive diabetic rats.

Aim: Peroxisomes are known to play a role in cellular oxidative stress during pathogenesis of diabetes and hypertension. We reported earlier that FPTIII (a farnesyl protein transferase inhibitor) attenuates ischemia-reperfusion injury and renal dysfunction in diabetic hypertensive (DH) rats. In this study, we have examined the effect of FPTIII on peroxisomal enzymes in relation to oxidative stress in kidneys of DH rats.

Early inhibition of EGFR signaling prevents diabetes-induced up-regulation of multiple gene pathways in the mesenteric vasculature.

Diabetes mellitus is associated with vascular complications including an impairment of vascular function and alterations in the reactivity of blood vessels to vasoactive hormones. However, the signaling mechanisms leading to vascular dysfunction in diabetes are not fully understood. This microarray-based study was designed to identify differential gene expression between the normal and diabetic mesenteric vasculature and to investigate the effect of inhibiting epidermal growth factor receptor (EGFR) signaling on global gene expression in the mesenteric bed of streptozotocin (STZ)-induced diabetic rats.

Role of epidermal growth factor receptor (EGFR) in corneal remodelling in diabetes.

Purpose: This study examined the role of epidermal growth factor receptor (EGFR) signalling on the organization and remodelling of collagen fibrils (CFs) and proteoglycans (PGs) in the stroma of diabetic rat cornea.

Methods: Diabetes was induced in female Wistar rats (n = 5) by streptozotocin (STZ) injection (55 mg/kg). Treatment with a selective inhibitor of EGFR tyrosine kinase, AG1478, was started on the same day as the induction of diabetes and administered every other day for 4 weeks.

Global upregulation of gene expression associated with renal dysfunction in DOCA-salt-induced hypertensive rats occurs via signaling cascades involving epidermal growth factor receptor: a microarray analysis.

Renal dysfunction is a major cause of morbidity and mortality in patients with hypertension. In an attempt to understand the molecular mechanisms leading to renal dysfunction and in particular that of epidermal growth factor receptor (EGFR) and RasGTPase signaling, we analyzed global gene expression changes in the kidneys of deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats with and without treatment with AG1478, a selective inhibitor of EGFR tyrosine kinase, or FPTIII, a farnesyl transferase inhibitor known to inhibit RasGTPase. Microarray-based global gene expression analysis was performed in triplicate for each rat kidney taken from normotensive Wistar rats, DOCA-salt hypertensive (DH) rats, DH rats treated with AG1478, or DH rats treated with FPTIII.

Inhibition of Ras-GTPase signaling by FPTIII ameliorates development of cardiovascular dysfunction in diabetic-hypertensive rats.

We studied the effect an inhibitor of Ras-GTPase (FPTIII, 1.5 mg/kg alt diem for 4 weeks) on mean arterial pressure (MAP), urine protein, vascular reactivity and cardiac function in streptozotocin (STZ)-induced diabetes in control normotensive (WKY) and spontaneously hypertensive rats (SHR). The increased urinary protein in STZ-treated WKY (D-WKY) and STZ-treated SHR (D-SHR) were significantly lower in FPTIII treated D-WKY and D-SHR.