Renin-angiotensin system (RAS) inhibition can attenuate the effects of aging on renal function and structure; however, its effect on mitochondrial aging is unknown. To investigate whether an angiotensin-converting enzyme inhibitor (enalapril) or an angiotensin II receptor blocker (losartan) could mitigate age-associated changes in kidney mitochondria, male Wistar rats (14 mo old) received during 8 mo water containing either enalapril (10 mg/kg/day) (Enal), or losartan (30 mg/kg/day) (Los), or no additions (Old). Four-month-old untreated rats (Young) were also studied. In Old rats mitochondrial respiratory control, ADP/O, nitric oxide synthase activity, and uncoupling protein 2 levels were lower (46, 42, 27, and 76%, respectively), and Mn-SOD activity was higher (70%) than in Young, Enal, and Los rats. In Old rats mitochondrial hydrogen peroxide production was higher than in both Young (197%) and Enal or Los (40%) rats. In Old rats, kidney GSH/GSSG was lower than in both Young (80%) and Enal (57%) or Los (68%) rats. In Old rats electron microscopy showed effacement of microvilli in tubular epithelial cells, ill-defined mitochondrial cristae, lower mitochondrial numbers, and enhanced number of osmiophilic bodies relative to Young, Enal, or Los rats. In conclusion, enalapril and losartan can protect against both age-related mitochondrial dysfunction and ultrastructural alterations, underscoring the role of RAS in the aging process. An association with oxidative stress modulation is suggested.

Experimental studies indicate that angiotensin II (ANG II) through its type 1 receptor (AT1) promotes cardiovascular hypertrophy and fibrosis. Therefore, the aim of this study was to analyze whether chronic long-term inhibition of the renin-angiotensin system (RAS) can prevent most of the deleterious effects due to aging in the cardiovascular system of the normal rat. The main objective was to compare two strategies of ANG II blockade: a converting enzyme inhibitor (CEI) and an AT1 receptor blocker (AT1RB). A control group remained untreated; treatment was initiated 2 wk after weaning. A CEI, enalapril (10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), or an AT 1RB, losartan (30 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), was used to inhibit the RAS. Systolic blood pressure, body weight, and water and food intake were recorded over the whole experimental period. Heart, aorta, and mesenteric artery weight as well as histological analysis of cardiovascular structure were performed at 6 and 18 mo. Twenty animals in each of the three experimental groups were allowed to die spontaneously. The results demonstrated a significant protective effect on the function and structure of the cardiovascular system in all treated animals. Changes observed at 18 mo of age in the hearts and aortas were quite significant, but each treatment completely abolished this deterioration. The similarity between the results detected with either enalapril or losartan treatment clearly indicates that most of the effects are exerted through AT 1 receptors. An outstanding finding was the significant and similar prolongation of life span in both groups of treated animals compared with untreated control animals. losartan; enalapril; heart; aorta; life span THE NATURAL PROCESS OF AGING is related to a progressive modification, and ultimately, a loss of organ function. These alterations are common to all species. In general, there is a correlation between the structural and functional changes associated with aging. In mammals, degenerative processes such as arteriosclerosis, the development of senile plaques in the brain, and the replacement of functional parenchyma by fibroconnective tissue in a variety of organs are considered manifestations of aging (19,41).Ultrastructurally, a reduction in the number of cellular organelles such as mitochondria is common in the aging process (13,21,36). Lifelong free radical production could play a main role in the reduction of the number and in both structural and functional mitochondria modifications (6,20,38). It has been widely postulated that reactive oxygen species (ROS) are causally involved in the aging process (19,20). In this sense, earlier data (4, 17) have confirmed that nitric oxide synthase (NOS) activity in the aorta and nitric oxide (NO) production diminish with age, whereas chronic long-term administration of angiotensin II (ANG II) inhibitors maintains endothelial NOS activity in old animals. Moreover, the mitochondria from hearts of aged rats chronically treated with ANG II inhibitors were found to have increased NOS activity and decrease...

Mitochondria are energy-producing organelles that conduct other key cellular tasks. Thus, mitochondrial damage may impair various aspects of tissue functioning. Mitochondria generate oxygen- and nitrogen-derived oxidants, being themselves major oxidation targets. Dysfunctional mitochondria seem to contribute to the pathophysiology of hypertension, cardiac failure, the metabolic syndrome, obesity, diabetes mellitus, renal disease, atherosclerosis, and aging. Mitochondrial proteins and metabolic intermediates participate in various cellular processes, apart from their well-known roles in energy metabolism. This emphasizes the participation of dysfunctional mitochondria in disease, notwithstanding that most evidences supporting this concept come from animal and cultured-cell studies. Mitochondrial oxidant production is altered by several factors related to vascular pathophysiology. Among these, angiotensin-II stimulates mitochondrial oxidant release leading to energy metabolism depression. By lowering mitochondrial oxidant production, angiotensin-II inhibition enhances energy production and protects mitochondrial structure. This seems to be one of the mechanisms underlying the benefits of angiotensin-II inhibition in hypertension, diabetes, and aging rodent models. If some of these findings can be reproduced in humans, they would provide a new perspective on the implications that RAS-blockade can offer as a therapeutic strategy. This review intends to present available information pointing to mitochondria as targets for therapeutic Ang-II blockade in human renal and CV disease.

This review attempts to show that there may be a relationship between inflammatory processes induced by chronic overstimulation of the renin-angiotensin system (RAS) and the worldwide deficiency of vitamin D (VitD) and that both disorders are probably associated with environmental factors. Low VitD levels represent a risk factor for several apparently different diseases, such as infectious, autoimmune, neurodegenerative, and cardiovascular diseases, as well as diabetes, osteoporosis, and cancer. Moreover, VitD insufficiency seems to predispose to hypertension, metabolic syndrome, left ventricular hypertrophy, heart failure, and chronic vascular inflammation. On the other hand, inappropriate stimulation of the RAS has also been associated with the pathogenesis of hypertension, heart attack, stroke, and hypertrophy of the left ventricle and vascular smooth muscle cells. Because VitD receptors (VDRs) and RAS receptors are almost distributed in the same tissues, a possible link between VitD and the RAS is even more plausible. Furthermore, from an evolutionary point of view, both systems were developed simultaneously, actively participating in the regulation of inflammatory and immunological mechanisms. Changes in RAS activity and activation of the VDR seem to be inversely related; thus any changes in one of these systems would have a completely opposite effect on the other, making it possible to speculate that the two systems could have a feedback relationship. In fact, the pandemic of VitD deficiency could be the other face of increased RAS activity, which probably causes lower activity or lower levels of VitD. Finally, from a therapeutic point of view, the combination of RAS blockade and VDR stimulation appears to be more effective than either RAS blockade or VDR stimulation individually.

Abstract-Oxidative stress is involved in both the pathogenesis and complications of diabetes. ACE inhibitors can slow the progression of cardiac and renal impairments related to diabetes. The effect of enalapril treatment on oxidative stress and tissue injury was studied in hearts, kidneys, and livers from streptozotocin-induced diabetic rats. Twenty-four rats were divided into the following groups: streptozotocin (65 mg/kg, single intraperitoneal dose), streptozotocinϩenalapril (20 mg enalapril/L drinking water), and control (intraperitoneal saline). Seven months after streptozotocin injection, organs were studied by light microscopy and collagen III immunolabeling. Tissue lesions and collagen labeling were graded by a semiquantitative score (0 to 4). Total glutathione content, glutathione redox status (reduced/oxidized glutathione), antioxidant enzyme activities, protein-associated sulfhydryls, thiobarbituric acid-reactive substances, and fluorescent chromolipids were determined in tissue homogenates. Glycemia was higher in both the streptozotocin and streptozotocinϩenalapril groups relative to the control group. In the streptozotocin group, creatinine clearance and body weight were lower, and systolic blood pressure and urinary albumin excretion were higher than in the streptozotocinϩenalapril and control groups. Heart, kidney, and liver lesion/labeling scores were significantly higher in the streptozotocin group compared with the streptozotocinϩenalapril and control groups. Kidney and liver total glutathione was lower in the streptozotocin group relative to the control group (PϽ0.05). Enalapril treatment significantly attenuated the reduction of total glutathione. In the heart, kidney, and liver, both glutathione and proteins were relatively more oxidized in the streptozotocin group relative to the control group (PϽ0.05). Protein and glutathione oxidation were attenuated in the streptozotocinϩenalapril group in the 3 tissues studied (PϽ0.05). Enalapril treatment attenuated the oxidation of lipids in the heart and kidney (PϽ0.05). Tissue fibrosis scores were inversely correlated with (1) both total glutathione and reduced/oxidized glutathione in heart, kidney, and liver and (2) glutathione reductase activity in the kidney. These results suggest that in streptozotocin-induced diabetic rats, the protective action of enalapril might be mediated, at least in part, by its effect on tissue oxidant/antioxidant status.

Inserra. Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine. Am J Physiol Regul Integr Comp Physiol 290: R1616 -R1625, 2006. First published January 12, 2006 doi:10.1152/ajpregu.00615.2005.-Mitochondrial dysfunction is associated with cardiovascular damage; however, data on a possible association with kidney damage are scarce. Here, we aimed at investigating whether 1) kidney impairment is related to mitochondrial dysfunction; and 2) ANG II blockade, compared with Ca 2ϩ channel blockade, can reverse potential mitochondrial changes in hypertension. Eight-week-old male spontaneously hypertensive rats (SHR) received water containing losartan (40 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 , SHRϩLos), amlodipine (3 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 , SHRϩAmlo), or no additions (SHR) for 6 mo. Wistar-Kyoto rats (WKY) were normotensive controls. Glomerular and tubulointerstitial damage, systolic blood pressure, and proteinuria were higher, and creatinine clearance was lower in SHR vs. SHRϩLos and WKY. In SHRϩAmlo, blood pressure was similar to WKY, kidney function was similar to SHR, and renal lesions were lower than in SHR, but higher than in SHRϩLos. In kidney mitochondria from SHR and SHRϩAmlo, membrane potential, nitric oxide synthase, manganese-superoxide dismutase and cytochrome oxidase activities, and uncoupling protein-2 content were lower than in SHRϩLos and WKY. In SHR and SHRϩAmlo, mitochondrial H 2O2 production was higher than in SHRϩLos and WKY. Renal glutathione content was lower in SHRϩAmlo relative to SHR, SHRϩLos, and WKY. In SHR and SHRϩAmlo, glutathione was relatively more oxidized than in SHRϩLos and WKY. Tubulointerstitial ␣-smooth muscle actin labeling was inversely related to manganese-superoxide dismutase activity and uncoupling protein-2 content. These findings suggest that oxidant stress is associated with renal mitochondrial dysfunction in SHR. The mitochondrial-antioxidant actions of losartan may be an additional or alternative way to explain some of the beneficial effects of AT 1-receptor antagonists. kidney disease; nitric oxide; mitochondria; oxidative stress; hypertension ARTERIAL HYPERTENSION IS ONE of the main causes of end-stage renal failure and is also an important risk factor for the progression of glomerular and tubulointerstitial diseases to chronic renal failure (31).The pathogenesis of renal damage from hypertension is incompletely understood. A possible explanation is an increased production of oxidants in the vasculature (2, 30) and the kidney (56), a well-documented finding in experimental and clinical hypertension. However, the pathways that lead from oxidant-induced damage to cellular function decay are poorly identified.Mitochondria are energy producing organelles that also conduct other key cellular tasks. They are involved in the regulation of tissue oxygen gradients (54), the modulation of apoptosis (9), and H 2 O 2 signaling (6). Hence, mitochondrial damage may lead to the impairment of various aspects of tissue functioning.Hypertension is...

Obesity and related diseases are an important and growing health concern in the United States and around the world. Soft drinks and other sugar-sweetened beverages are now the primary sources of added sugars in Americans' diets. The metabolic syndrome is a cluster of common pathologies, including abdominal obesity linked to an excess of visceral fat, fatty liver, insulin resistance, hyperinsulinemia, dyslipidemia, and hypertension. Trends in all of these alterations are related to the consumption of dietary fructose and the introduction of high-fructose corn syrup (HFCS) as a sweetener in soft drinks and other foods. Experimental and clinical evidence suggests a progressive association between HFCS consumption, obesity, and the other injury processes. However, experimental HFCS consumption seems to produce some of the changes associated with metabolic syndrome even without increasing the body weight. Metabolic damage associated with HFCS probably is not limited to obesity-pathway mechanisms.

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