Involvement of sex hormones, oxidative stress, ACE and ACE2 activity in the impairment of renal function and remodelling in SHR.

Aims: Hypertension is a relevant sex and sex hormones-dependent risk factor where the cardiovascular and renal health of the population are concerned. Men experience greater losses of renal function (RF) than women, but the mechanisms remain somewhat unclear. Our goal was to evaluate the relationship between oxidative stress (OS), angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activities and RF in male and female SHR.

The caveolin-1 regulated protein follistatin protects against diabetic kidney disease.

Glomerular matrix protein accumulation, mediated largely by mesangial cells, is central to the pathogenesis of diabetic kidney disease. Our previous studies showed that the membrane microdomains caveolae and their marker protein caveolin-1 regulate matrix protein synthesis in mesangial cells in response to diabetogenic stimuli, and that caveolin-1 knockout mice are protected against diabetic kidney disease. In a screen to identify the molecular mechanism underlying this protection, we also established that secreted antifibrotic glycoprotein follistatin is significantly upregulated by caveolin-1 deletion.

Follistatin Protects Against Glomerular Mesangial Cell Apoptosis and Oxidative Stress to Ameliorate Chronic Kidney Disease.

Interventions to inhibit oxidative stress and apoptosis, important pathogenic contributors toward the progression of chronic kidney disease (CKD), are not well established. Here, we investigated the role of a transforming growth factor beta (TGFβ) superfamily neutralizing protein, follistatin (FST), in the regulation of apoptosis and oxidative stress in glomerular mesangial cells (MCs) and in the progression of CKD. The endoplasmic reticulum (ER) stress inducer thapsigargin (Tg), known to cause MC apoptosis, led to a post-translational increase in the expression of FST.

Caveolin-1 regulation of Sp1 controls production of the antifibrotic protein follistatin in kidney mesangial cells.

Background: We previously showed that caveolin-1 (cav-1), an integral membrane protein, is required for the synthesis of matrix proteins by glomerular mesangial cells (MC). In a previous study to understand how cav-1 is involved in regulating matrix production, we had identified significant upregulation of the antifibrotic protein follistatin in cav-1 knockout MC. Follistatin inhibits the profibrotic effects of several members of the transforming growth factor beta superfamily, in particular the activins.

Increased ROS production and DNA damage in monocytes are biomarkers of aging and atherosclerosis.

Background: New evidence demonstrates that aging and dyslipidemia are closely associated with oxidative stress, DNA damage and apoptosis in some cells and extravascular tissues. However, in monocytes, which are naturally involved in progression and/or resolution of plaque in atherosclerosis, this concurrence has not yet been fully investigated. In this study, we evaluated the influence of aging and hypercholesterolemia on serum pro-inflammatory cytokines, oxidative stress, DNA damage and apoptosis in monocytes from apolipoprotein E-deficient (apoE) mice compared with age-matched wild-type C57BL/6 (WT) mice.

Beneficial Morphofunctional Changes Promoted by Sildenafil in Resistance Vessels in the Angiotensin II-Induced Hypertension Model.

Background: By acting on multiple targets and promoting diverse actions, angiotensin II (Ang II) plays a pivotal role in vascular function. Recent studies suggested that phosphodiesterase-5 (PDE-5) inhibitors exhibit therapeutic effects in cardiovascular diseases. Here, the effects of sildenafil on vascular disturbances were analyzed in a mouse model of Ang II-induced hypertension.

Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice.

Background/aims: The atherosclerotic apolipoprotein E-deficient (apoE-/-) mouse exhibits impaired vasodilation and enhanced vasoconstriction responsiveness. The objectives of this study were: a) to determine the relative contribution of cyclooxygenases (Cox-1 and Cox-2), thromboxane A2 (TXA2) and endothelin-1 (ET-1) to enhancing vascular hyperresponsiveness in this model of atherosclerosis and b) to investigate the beneficial effects of the phosphodiesterase 5 inhibitor sildenafil on this endothelial dysfunction.

Methods: Adult male apoE-/- mice were treated with sildenafil (40 mg/kg/day, for 3 weeks) and compared with non-treated ApoE-/- and wild-type mice.

Increased Blood Pressure Variability Prior to Chronic Kidney Disease Exacerbates Renal Dysfunction in Rats.

Increased blood pressure variability (BPV), which can be experimentally induced by sinoaortic denervation (SAD), has emerged as a new marker of the prognosis of cardiovascular and renal outcomes. Considering that increased BPV can lead to organ-damage, the goal of the present study was to evaluate the effects of SAD on renal function in an experimental model of chronic kidney disease (CKD). SAD was performed in male Wistar rats 2 weeks before 5/6 nephrectomy and the animals were evaluated 4 weeks after the induction of CKD.

Coadjuvants in the Diabetic Complications: Nutraceuticals and Drugs with Pleiotropic Effects.

Because diabetes mellitus (DM) is a multifactorial metabolic disease, its prevention and treatment has been a constant challenge for basic and clinical investigators focused on translating their discoveries into clinical treatment of this complex disorder. In this review, we highlight recent experimental and clinical evidences of potential coadjuvants in the management of DM, such as polyphenols (quercetin, resveratrol and silymarin), cultured probiotic microorganisms and drugs acting through direct/indirect or pleiotropic effects on glycemic control in DM. Among several options, we highlight new promising therapeutic coadjuvants, including chemical scavengers, the probiotic kefir and the phosphodiesterase 5 inhibitors, which besides the reduction of hyperglycemia and ameliorate insulin resistance, they reduce oxidative stress and improve endothelial dysfunction in the systemic vascular circulation.

Tributyltin chloride induces renal dysfunction by inflammation and oxidative stress in female rats.

Tributyltin chloride (TBT) is an organometallic pollutant that is used as a biocide in antifouling paints. TBT induces several toxic and endocrine-disrupting effects. However, studies evaluating the effects of TBT on renal function are rare.

Effects of Kefir on the Cardiac Autonomic Tones and Baroreflex Sensitivity in Spontaneously Hypertensive Rats.

Aims: It has been previously shown that the probiotic kefir (a symbiotic matrix containing acid bacteria and yeasts) attenuated the hypertension and the endothelial dysfunction in spontaneously hypertensive rats (SHR). In the present study, the effect of chronic administration of kefir on the cardiac autonomic control of heart rate (HR) and baroreflex sensitivity (BRS) in SHR was evaluated.

Methods: SHR were treated with kefir (0.

Dioclea violacea lectin ameliorates oxidative stress and renal dysfunction in an experimental model of acute kidney injury.

Acute kidney injury (AKI) is characterized by rapid and potentially reversible decline in renal function; however, the current management for AKI is nonspecific and associated with limited supportive care. Considering the need for more novel therapeutic approaches, we believe that lectins from Dioclea violacea (Dvl), based on their anti-inflammatory properties, could be beneficial for the treatment of AKI induced by renal ischemia/reperfusion (IR). Dvl (1 mg/kg, i.

Sildenafil prevents renal dysfunction in contrast media-induced nephropathy in Wistar rats.

Contrast-induced nephropathy (CIN) is an iatrogenic medical event in stable cardiology patients that may lead to acute renal failure. There is no current successful therapy to manage CIN. Increasing evidence in experimental models and humans has suggested that this disease is associated with renal tubular and vascular injury triggered by oxidative stress.

Chronic administration of the probiotic kefir improves the endothelial function in spontaneously hypertensive rats.

Background: The beverage obtained by fermentation of milk with kefir grains, a complex matrix containing acid bacteria and yeasts, has been shown to have beneficial effects in various diseases. However, its effects on hypertension and endothelial dysfunction are not yet clear. In this study, we evaluated the effects of kefir on endothelial cells and vascular responsiveness in spontaneously hypertensive rats (SHR).

Novel Therapeutic Targets for Phosphodiesterase 5 Inhibitors: current state-of-the-art on systemic arterial hypertension and atherosclerosis.

The usefulness of selective inhibitors of phosphodiesterase 5 (PDE5) is well known, first for the treatment of male erectile dysfunction and more recently for pulmonary hypertension. The discovery that PDE5 is present in the systemic artery endothelium and smooth muscle cells led investigators to test the extra sexual effects of sildenafil, the first and most investigated PDE5 inhibitor, in diseases affecting the systemic arteries. Cumulative data from experimental and clinical studies have revealed beneficial effects of sildenafil on systemic arterial hypertension and its target organs, such as the heart, kidneys and vasculature.

Reactive oxygen species contribute to dysfunction of bone marrow hematopoietic stem cells in aged C57BL/6 J mice.

Background: Stem cells of intensely regenerative tissues are susceptible to cellular damage. Although the response to this process in hematopoietic stem cells (HSCs) is crucial, the mechanisms by which hematopoietic homeostasis is sustained are not completely understood. Aging increases reactive oxygen species (ROS) levels and inflammation, which contribute to increased proliferation, senescence and/or apoptosis, leading to self-renewal premature exhaustion.

The protective effects of oral low-dose quercetin on diabetic nephropathy in hypercholesterolemic mice.

Aims: Diabetic nephropathy (DN) is one of the most important causes of chronic renal disease, and the incidence of DN is increasing worldwide. Considering our previous report (Gomes et al., 2014) indicating that chronic treatment with oral low-dose quercetin (10 mg/Kg) demonstrated anti-oxidative, anti-apoptotic and renoprotective effects in the C57BL/6J model of DN, we investigated whether this flavonoid could also have beneficial effects in concurrent DN and spontaneous atherosclerosis using the apolipoprotein E-deficient mouse (apoE(-/-)).

Sildenafil Improves Vascular Endothelial Structure and Function in Renovascular Hypertension.

In translational medicine, the discovery of new drugs or new potential uses for currently available drugs is crucial for treating the resistant hypertension associated with renal artery stenosis. The phosphodiesterase 5 inhibitor sildenafil has been shown to reduce blood pressure and to improve the endothelium-dependent relaxation in the two kidney, one clip (2K1C) mouse model of renovascular hypertension. In the present study, we evaluated the effects of sildenafil (40 mg/kg/day for two weeks) on the endothelial structure and contractile function in mesenteric resistance arteries 28 days after clipping the renal artery.

Mechanisms of enhanced vasoconstriction in the mouse model of atherosclerosis: the beneficial effects of sildenafil.

Sildenafil ameliorates aortic relaxations in apolipoprotein E knockout (apoE) mice. Now, we tested the hypothesis that endothelial dysfunction (ED) in this model is characterized by contractile hyperresponsiveness to phenylephrine (PE) and that this abnormality may be repaired using sildenafil. The aortic rings were evaluated in apoE mice treated with sildenafil (apoE-sil, 40 mg/kg/day) and compared with apoE and wild-type (WT) mice administered with vehicle (veh).

Tributyltin chloride leads to adiposity and impairs metabolic functions in the rat liver and pancreas.

Tributyltin chloride (TBT) is an environmental contaminant used in antifouling paints of boats. Endocrine disruptor effects of TBT are well established in animal models. However, the adverse effects on metabolism are less well understood.

Endogenous female sex hormones delay the development of renal dysfunction in apolipoprotein E-deficient mice.

Background: Hypercholesterolemia is a well-established risk factor for the development of kidney injury. Considering that female sex hormones may play a preventative role in both cardiovascular and renal diseases, the aim of the present study was to evaluate the effects of female sex hormones on hypercholesterolemia-induced renal dysfunction.

Methods: Apolipoprotein E-deficient (ApoE) and C57 control female mice underwent an ovariectomy (OVX) or sham surgery and after 2 months, creatinine clearance, uremia and proteinuria were determined.

Inhibition of phosphodiesterase 5 restores endothelial function in renovascular hypertension.

Background: The clipping of an artery supplying one of the two kidneys (2K1C) activates the renin-angiotensin (Ang) system (RAS), resulting in hypertension and endothelial dysfunction. Recently, we demonstrated the intrarenal beneficial effects of sildenafil on the high levels of Ang II and reactive oxygen species (ROS) and on high blood pressure (BP) in 2K1C mice. Thus, in the present study, we tested the hypothesis that sildenafil improves endothelial function in hypertensive 2K1C mice by improving the NO/ROS balance.

Sildenafil ameliorates oxidative stress and DNA damage in the stenotic kidneys in mice with renovascular hypertension.

Background: Oxidative stress and DNA damage have been implicated in the pathogenesis of renovascular hypertension induced by renal artery stenosis in the two-kidney, one-clip (2K1C) Goldblatt model. Considering our previous report indicating that the chronic blockade of phosphodiesterase 5 with sildenafil (Viagra) has marked beneficial effects on oxidative stress and DNA damage, we tested the hypothesis that sildenafil could also protect the stenotic kidneys of 2K1C hypertensive mice against oxidative stress and genotoxicity.

Methods: The experiments were performed with C57BL6 mice subjected to renovascular hypertension by left renal artery clipping.

Sildenafil restores endothelial function in the apolipoprotein E knockout mouse.

Background: Atherosclerosis is an inflammatory process of the arterial walls and is initiated by endothelial dysfunction accompanied by an imbalance in the production of reactive oxygen species (ROS) and nitric oxide (NO). Sildenafil, a selective phosphodiesterase-5 (PDE5) inhibitor used for erectile dysfunction, exerts its cardiovascular effects by enhancing the effects of NO. The aim of this study was to investigate the influence of sildenafil on endothelial function and atherosclerosis progression in apolipoprotein E knockout (apoE-/-) mice.

Cardiac-autonomic imbalance and baroreflex dysfunction in the renovascular Angiotensin-dependent hypertensive mouse.

Mouse models provide powerful tools for studying the mechanisms underlying the dysfunction of the autonomic reflex control of cardiovascular function and those involved in cardiovascular diseases. The established murine model of two-kidney, one-clip (2K1C) angiotensin II-dependent hypertension represents a useful tool for studying the neural control of cardiovascular function. In this paper, we discuss the main contributions from our laboratory and others regarding cardiac-autonomic imbalance and baroreflex dysfunction.