Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine

Cavanagh, Elena M.V. de; Toblli, Jorge Eduardo; Ferder, León; Piotrkowski, Bárbara; Stella, Inés; Inserra, Felipe

doi:10.1152/ajpregu.00615.2005

Cited by 107 publications

(95 citation statements)

References 57 publications

(46 reference statements)

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“…Mitochondria are degraded in lysosomes by a process known as "mitophagy" (28). Previous studies have shown that AT1R-dependent pathways augment ROS production, which is known to promote mitophagy and reduce mitochondrial content in rat kidney (29,30). Moreover, in our experiments, an AT1R-dependent increase in lysosomes has been observed in AngII-treated C2C12 cells (data not shown).…”

Section: Discussionsupporting

confidence: 65%

Angiotensin II Reduces Mitochondrial Content in Skeletal Muscle and Affects Glycemic Control

et al. 2009

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OBJECTIVE— Blockade of angiotensin (Ang) II has been shown to prevent new-onset type 2 diabetes. We focused on the effects of AngII on muscle mitochondria, especially on their biogenesis, as an underlining mechanism of type 2 diabetes. RESEARCH DESIGN AND METHODS— C2C12 cells and C57bl/6 mice were used to examine roles for AngII in the regulation of muscle mitochondria and to explore whether the effect was mediated by type 1 AngII receptor (AT1R) or type 2 receptor (AT2R). RESULTS— C2C12 cells treated with 10 −8 –10 −6 mol/l AngII reduced the mitochondrial content associated with downregulation of the genes involved in mitochondrial biogenesis. The action of AngII was diminished by blockade of AT2R but not AT1R, whereas overexpression of AT2R augmented the effect. AngII increased mitochondrial ROS and decreased mitochondrial membrane potential, and these effects of AngII were significantly suppressed by blockade of either AT1R or AT2R. Chronic AngII infusion in mice also reduced muscle mitochondrial content in association with increased intramuscular triglyceride and deteriorated glycemic control. The AngII-induced reduction in muscle mitochondria in mice was partially, but significantly, reversed by blockade of either AT1R or AT2R, associated with increased fat oxidation, decreased muscle triglyceride, and improved glucose tolerance. Genes involved in mitochondrial biogenesis were decreased via AT2R but not AT1R under these in vivo conditions. CONCLUSIONS— Taken together, these findings imply the novel roles for AngII in the regulation of muscle mitochondria and lipid metabolism. AngII reduces mitochondrial content possibly through AT1R-dependent augmentation of their degradation and AT2R-dependent direct suppression of their biogenesis.

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Section: Discussionsupporting

confidence: 65%

Angiotensin II Reduces Mitochondrial Content in Skeletal Muscle and Affects Glycemic Control

et al. 2009

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“…In addition, AT 1 R blockers have been reported to reduce agerelated mitochondrial dysfunction, attenuate hypertension-induced renal mitochondrial dysfunction, and protect against cardiac mitochondrial dysfunction in the setting of acute ischemia (39,40). Interestingly, disruption of AT 1 Rs was associated with an increased number of mitochondria and up-regulation of the prosurvival genes nicotinamide phosphoribosyltransferase (Nampt) and sirtuin 3 (Sirt3) in the kidney, leading to marked prolongation of life span in mice (41).…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of a functional mitochondrial angiotensin system

Abadir

Foster²,

Crow

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

245

251

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The renin-angiotensin (Ang) system regulates multiple physiological functions through Ang II type 1 and type 2 receptors. Prior studies suggest an intracellular pool of Ang II that may be released in an autocrine manner upon stretch to activate surface membrane Ang receptors. Alternatively, an intracellular renin-Ang system has been proposed, with a primary focus on nuclear Ang receptors. A mitochondrial Ang system has not been previously described. Here we report that functional Ang II type 2 receptors are present on mitochondrial inner membranes and are colocalized with endogenous Ang. We demonstrate that activation of the mitochondrial Ang system is coupled to mitochondrial nitric oxide production and can modulate respiration. In addition, we present evidence of age-related changes in mitochondrial Ang receptor expression, i.e., increased mitochondrial Ang II type 1 receptor and decreased type 2 receptor density that is reversed by chronic treatment with the Ang II type 1 receptor blocker losartan. The presence of a functional Ang system in human mitochondria provides a foundation for understanding the interaction between mitochondria and chronic disease states and reveals potential therapeutic targets for optimizing mitochondrial function and decreasing chronic disease burden with aging.

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“…For example, renal mitochondrial dysfunction in spontaneously hypertensive rats was attenuated by treatment with the ARB losartan. 39 de Cavanagh et al reported that mitochondrial dysfunction and mitochondrial ultrastructural changes occur in aged rat kidney, and these changes are prevented by the ARB losartan. 40 In that study, the authors suggested that the association of ARBs with oxidative stress modulation might be effective in mitochondrial protection.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

Satoh

Fujimoto

Horike

et al. 2011

Laboratory Investigation

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Decreased expression of vascular endothelial growth factor (VEGF) in the renal tubules is thought to cause progressive loss of the renal microvasculature with age. Mitochondrial dysfunction may be a principal phenomenon underlying the process of aging. The relation between VEGF expression and mitochondrial dysfunction in aging is not fully understood. We hypothesized that mitochondrial dysfunction blocks VEGF expression and contributes to impaired angiogenesis in the aging kidney. The aim of this study was to assess the role of mitochondria in VEGF expression in the aging rat kidney. We evaluated the accumulation of 8-hydroxy-2 0 -deoxyguanosine in mitochondrial DNA, as well as mitochondrial dysfunction, as assessed by electron microscopy of mitochondrial structure and histochemical staining for respiratory chain complex IV, in aging rat kidney. An increase in hypoxic area and a decrease in peritubular capillaries were detected in the cortex of aging rat kidneys; however, upregulation of VEGF expression was not observed. The expression of VEGF in proximal tubular epithelial cells in response to hypoxia was suppressed by the mitochondrial electron transfer inhibitor myxothiazol. Mitochondrial DNA-deficient cells also failed to upregulate VEGF expression under hypoxic conditions. These results indicate that impairment of VEGF upregulation, possibly as a result of mitochondrial dysfunction, contributes to impaired angiogenesis, which in turn leads to renal injury in the aging rat kidney.

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Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine

Cited by 107 publications

References 57 publications

Angiotensin II Reduces Mitochondrial Content in Skeletal Muscle and Affects Glycemic Control

Angiotensin II Reduces Mitochondrial Content in Skeletal Muscle and Affects Glycemic Control

Identification and characterization of a functional mitochondrial angiotensin system

Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

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