Experimental model of lead nephropathy. I. Continuous high-dose lead administration

Experimental model of lead nephropathy. I. Continuous high-dose lead administration. This study followed the progression of lead nephropathy in male Sprague-Dawley rats (E) administered lead acetate (0.5%) continuously in drinking water for periods ranging from 1 to 12 months. Control animals (C) were pair-fed. Observations included renal pathology by light and electron microscopy, wet and dry kidney weights, and glomerular filtration rate (GFR) to assess renal function. Urinary excretion of lead, the enzymes N-acetyl-beta-D-glucosaminidase (NAG) and glutathione-S-transferase (GST), and brush border antigens (BB50, CG9, and HF5) were utilized to explore possible markers of kidney injury. GFR was increased significantly after three months of lead exposure, but was decreased significantly after 12 months. Kidney wet weights were significantly greater in E than C from three months on. Kidney dry weight/wet weight ratio was constant up to three months, but decreased in E at 12 months. Glomerular diameters were normal at all time periods; the nephromegaly was related primarily to hypertrophy of proximal tubules. Lead inclusion bodies were found in nuclei of proximal convoluted tubules and pars recta at all times. Tubular atrophy and interstitial fibrosis first appeared at six months, and increased in severity thereafter. Brush borders of proximal tubules were disrupted at one and three months, but recovered thereafter. Focal and segmental glomerulosclerosis was observed in 2 of 10 rats at 12 months. Arteries and arterioles remained normal at all time periods. Urinary NAG was elevated in E above C after three months of lead exposure. However, urinary NAG in C also increased with age, obscuring changes in the 12 month E rats. GST was elevated after three months of lead administration in E, not without an attendant age-related increase in C rats. In three-month E rats, urinary brush border antigens were increased above C, but were decreased at six and 12 months, correlating with the morphologic changes in brush border. We conclude that a high dose of lead in rats may initially stimulate both renal cortical hypertrophy and an increase in GFR. Later, the adverse effects of lead on the tubulointerstitium predominate, and GFR falls. The urinary marker, NAG, was abnormal in the early stages of the disease, but age-related changes obscured its utility at later stages; urinary GST appeared to be a more consistent marker of injury

Acute Lead Exposure Increases Arterial Pressure: Role of the Renin-Angiotensin System

Background: Chronic lead exposure causes hypertension and cardiovascular disease. Our purpose was to evaluate the effects of acute exposure to lead on arterial pressure and elucidate the early mechanisms involved in the development of lead-induced hypertension. Methodology/Principal Findings: Wistar rats were treated with lead acetate (i.v. bolus dose of 320 μg/Kg), and systolic arterial pressure, diastolic arterial pressure and heart rate were measured during 120 min. An increase in arterial pressure was found, and potential roles of the renin-angiotensin system, Na+,K+-ATPase and the autonomic reflexes in this change in the increase of arterial pressure found were evaluated. In anesthetized rats, lead exposure: 1) produced blood lead levels of 37±1.7 μg/dL, which is below the reference blood concentration (60 μg/dL); 2) increased systolic arterial pressure (Ct: 109±3 mmHg vs Pb: 120±4 mmHg); 3) increased ACE activity (27% compared to Ct) and Na+,K+-ATPase activity (125% compared to Ct); and 4) did not change the protein expression of the α1-subunit of Na+,K+-ATPase, AT1 and AT2. Pre-treatment with an AT1 receptor blocker (losartan, 10 mg/Kg) or an ACE inhibitor (enalapril, 5 mg/Kg) blocked the lead-induced increase of arterial pressure. However, a ganglionic blockade (hexamethonium, 20 mg/Kg) did not prevent lead's hypertensive effect. Conclusion: Acute exposure to lead below the reference blood concentration increases systolic arterial pressure by increasing angiotensin II levels due to ACE activation. These findings offer further evidence that acute exposure to lead can trigger early mechanisms of hypertension development and might be an environmental risk factor for cardiovascular diseaseThis study was supported by grants from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico)/FAPES (Fundação de Amparo à Pesquisa do Espírito Santo)/FUNCITEC (Fundação de Ciência e Tecnologia)(39767531/07), Brazil and from MCINN (Ministerio de Ciencia e Innovación) (SAF 2009- 07201) and ISCIII (Instituto de Salud Carlos III) (Red RECAVA- Red Temática de Investigación en Enfermedades Cardiovasculares del Instituto de Salud Carlos III, RD06/0014/0011), Spai

Salt restriction in kidney disease—a missed therapeutic opportunity?

The importance of salt restriction in the treatment of patients with renal disease has remained highly controversial. In the following we marshal the current evidence that salt plays a definite role in the genesis of hypertension and target organ damage, point to practical problems of salt restriction, and report on novel pathomechanisms of how salt affects blood pressure and causes target organ damage

Cardiovascular effects of lead exposure.

Several epidemiological and clinical studies have found a link between chronic lead exposure and elevated blood pressure. In addition, a few population studies have shown possible connection between lead exposure and other cardiovascular disorders including ischaemic coronary heart disease, cerebrovascular accidents, and peripheral vascular disease. The causal link between chronic lead exposure and hypertension (HTN) has been confirmed by several studies in experimental animals. In addition, the effects of lead on the heart and vascular function have been explored in a limited number of in vivo and in vitro studies. The in vivo, ex vivo and in vitro studies conducted in laboratory animal, cultured cells and isolated tissues have helped to elucidate many of the mechanisms by which lead exposure can cause HTN and cardiovascular disease. This review is intended to provide an overview of the epidemiology and the underlying mechanisms of lead-associated HTN and cardiovascular disease