From Mitochondria to Disease: Role of the Renin-Angiotensin System

Abstract

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.

Mitochondrial ATP-sensitive potassium channels enhance angiotensin-induced oxidative damage and dopaminergic neuron degeneration. Relevance for aging-associated susceptibility to Parkinson’s disease

“…Similarly, we have recently shown that the effect of low/sublethal doses of neurotoxins on dopaminergic cell loss is amplified by angiotensin II via type 1 receptors and protein kinase C, leading to activation of the microglial NADPH oxidase and exacerbation of the glial inflammatory response, which increases ROS released by in microglia and dopaminergic neurons Rey et al 2007;Rodriguez-Pallares et al 2008). However, recent studies suggest that angiotensin II may stimulate not only cytosolic (i.e., via NADPH oxidase activation) but also mitochondrial-ROS generation in several tissues (de Cavanagh et al 2007;Zhang et al 2007), and numerous studies have shown that mitochondria play a major role in generation of oxidative stress, dopaminergic neuron degeneration, and aging (de Cavanagh et al 2007;Schapira 2008). This is consistent with recent studies that suggest cross-talk signaling between both the cytosolic NADPH oxidase and mitochondria in several types of cells, and that mitoK(ATP) play a major role in this interaction (Brandes 2005;Daiber 2010;Dikalova et al 2010;Doughan et al 2008).…”

“…It is well known that angiotensin II acts via type 1 receptors to release high levels of ROS mainly by activation of the NADPH oxidase (Qin et al 2004;Seshiah et al 2002;Touyz et al 2002), which was also observed in the nigrostriatal system Rey et al 2007;Rodriguez-Pallares et al 2008). However, recent studies suggest that angiotensin II may stimulate not only cytosolic but also mitochondrial-ROS generation (de Cavanagh et al 2007;Zhang et al 2007). In addition, a number of studies support a critical role for mitochondrial ATP-sensitive potassium channels [mito(KATP)] in modulating intracellular ROS (Mattson and Liu 2003;Costa and Garlid 2008).…”

Reactive oxygen species and vascular biology: implications in human hypertension

“…[56][57][58] Ang II-sensitive hypertension is also linked to mitochondrial-derived oxidative stress, as AT 1 receptor blockade attenuates H 2 O 2 production 59 and mitochondrial dysfunction in SHR, and in mice, Ang II infusion is associated with decreased expression of cardiac mitochondrial electron transport genes. 60 In deoxycorticosterone acetate-salt hypertension, mitochondrial-derived ROS, via endothelin-1/endothelin A receptors, has an important role in oxidative vascular damage. 61,62 In humans, mitochondrial heritability for systolic blood pressure is about 5% and mitochondrial effects may account for 35% of hypertensive pedigrees.…”

Acute adriamycin-induced cardiotoxicity is exacerbated by angiotension II

“…AP-1 arrange cytochrome c expression. So, Ang-II might be proposed to affect to cytochrome c though these interaction (de Cavanagh et al 2007). Interestingly, in rats that had undergone short or longterm administration of ADR, coadministration of angiotensin-converting enzyme (ACE) inhibitors were reported almost to restore the cardiac dysfunction.…”