Enhancing Mitochondrial Health to Treat Hypertension

Eirin, Alfonso; Lerman, Amir; Lerman, Lilach O.

doi:10.1007/s11906-018-0889-4

Cited by 23 publications

(20 citation statements)

References 70 publications

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“…It is widely accepted that in AKI and/or chronic kidney disease (CKD) such as DN, mitochondrial biogenesis is significantly affected, and thus could be one of the major reasons for renal tissue damage (Hall and Schuh, 2016;Bhargava and Schnellmann, 2017;Duann and Lin, 2017;Eirin et al, 2018). Surprisingly, little is known about mitochondrial function and biogenesis in SS hypertension.…”

Section: Discussionmentioning

confidence: 99%

Renal Glomerular Mitochondria Function in Salt-Sensitive Hypertension

et al. 2020

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Salt-sensitive (SS) hypertension is accompanied with an early onset of proteinuria, which results from the loss of glomerular podocytes. Here, we hypothesized that glomerular damage in the SS hypertension occurs in part due to mitochondria dysfunction, and we used a unique model of freshly isolated glomeruli to test this hypothesis. In order to mimic SS hypertension, we used Dahl SS rats, an established animal model. Animals were fed a 0.4% NaCl (normal salt, NS) diet or challenged with a high salt (HS) 4% NaCl diet for 21 days to induce an increase in blood pressure (BP). Similar to previous studies, we found that HS diet caused renal hypertrophy, increased BP, glomerulosclerosis, and renal lesions such as fibrosis and protein casts. We did not observe changes in mitochondrial biogenesis in the renal cortex or isolated glomeruli fractions. However, Seahorse assay performed on freshly isolated glomeruli revealed that basal mitochondrial respiration, maximal respiration, and spare respiratory capacity were lower in the HS compared to the NS group. Using confocal imaging and staining for mitochondrial H 2 O 2 using mitoPY1, we detected an intensified response to an acute H 2 O 2 application in the podocytes of the glomeruli isolated from the HS diet fed group. TEM analysis showed that glomerular mitochondria from the HS diet fed group have structural abnormalities (swelling, enlargement, less defined cristae). Therefore, we report that glomerular mitochondria in SS hypertension are functionally and structurally defective, and this impairment could eventually lead to loss of podocytes and proteinuria. Thus, the glomerular-mitochondria axis can be targeted in novel treatment strategies for hypertensive glomerulosclerosis.

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Section: Discussionmentioning

confidence: 99%

Renal Glomerular Mitochondria Function in Salt-Sensitive Hypertension

et al. 2020

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“…Excessive ROS production is recognized to accelerate HF progression (Wrigley et al, 2011). Thus, a current focus in the treatment of hypertension is identifying treatment modalities that improve mitochondrial health (Eirin et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Perindopril Improves Cardiac Function by Enhancing the Expression of SIRT3 and PGC-1α in a Rat Model of Isoproterenol-Induced Cardiomyopathy

Zhu

Chen

et al. 2020

Front. Pharmacol.

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Mitochondrial biosynthesis regulated by the PGC-1a-NRF1-TFAM pathway is considered a novel potential therapeutic target to treat heart failure (HF). Perindopril (PER) is an angiotensin-converting enzyme inhibitor that has proven efficacy in the prevention of HF; however, its mechanism is not well established. In this study, to investigate the mechanisms of PER in cardiac protection, a rat model of cardiomyopathy was established by continuous isoproterenol (ISO) stimulation. Changes in the body weight, heart weight index, echocardiography, histological staining, mitochondrial microstructure, and biochemical indicators were examined. Our results demonstrate that PER reduced myocardial remodeling, inhibited deterioration of cardiac function, and delayed HF onset in rats with ISO-induced cardiomyopathy. PER markedly reduced reactive oxygen species (ROS) production, increased the levels of antioxidant enzymes, inhibited mitochondrial structural destruction and increases the number of mitochondria, improved the function of the mitochondrial respiratory chain, and promoted ATP production in myocardial tissues. In addition, PER inhibited cytochrome C release in mitochondria and caspase-3 activation in the cytosol, thereby reducing the apoptosis of myocardial cells. Notably, PER remarkably up-regulated the mRNA and protein expression levels of Sirtuin 3 (SIRT3), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a), nuclear respiratory factor 1 (NRF1), and mitochondrial transcription factor A (TFAM) in myocardial cells. Collectively, our results suggest that PER induces mitochondrial biosynthesismediated enhancement of SIRT3 and PGC-1a expression, thereby improving the cardiac function in rats with ISO-induced cardiomyopathy.

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“…Critically, network-based drug repurposing has recently identified several candidates, such as irbesartan, paroxetine, sirolimus, melatonin and quinacrine, amongst others [ 180 ]. It has been suggested that angiotensin receptor blockers (ARBs) are mitochondrially protective [ 181 ], while anti-depressants, such as paroxetine, can inhibit mitochondrial function [ 182 ]. Sirolimus, or rapamycin, is actually one of the best studied calorie restriction mimetics as it modulates mammalian target of rapamycin (mTOR); it is anti-inflammatory and modulates mitochondrial function, and could play a key role in mitohormesis [ 183 ].…”

Section: Mitochondrial Function and Therapeutic Strategymentioning

confidence: 99%

SARS-CoV-2 and mitochondrial health: implications of lifestyle and ageing

Nunn

Guy²,

Brysch

et al. 2020

Immun Ageing

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Infection with SARs-COV-2 displays increasing fatality with age and underlying co-morbidity, in particular, with markers of the metabolic syndrome and diabetes, which seems to be associated with a “cytokine storm” and an altered immune response. This suggests that a key contributory factor could be immunosenescence that is both age-related and lifestyle-induced. As the immune system itself is heavily reliant on mitochondrial function, then maintaining a healthy mitochondrial system may play a key role in resisting the virus, both directly, and indirectly by ensuring a good vaccine response. Furthermore, as viruses in general, and quite possibly this new virus, have also evolved to modulate immunometabolism and thus mitochondrial function to ensure their replication, this could further stress cellular bioenergetics. Unlike most sedentary modern humans, one of the natural hosts for the virus, the bat, has to “exercise” regularly to find food, which continually provides a powerful adaptive stimulus to maintain functional muscle and mitochondria. In effect the bat is exposed to regular hormetic stimuli, which could provide clues on how to resist this virus. In this paper we review the data that might support the idea that mitochondrial health, induced by a healthy lifestyle, could be a key factor in resisting the virus, and for those people who are perhaps not in optimal health, treatments that could support mitochondrial function might be pivotal to their long-term recovery.

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Enhancing Mitochondrial Health to Treat Hypertension

Cited by 23 publications

References 70 publications

Renal Glomerular Mitochondria Function in Salt-Sensitive Hypertension

Renal Glomerular Mitochondria Function in Salt-Sensitive Hypertension

Perindopril Improves Cardiac Function by Enhancing the Expression of SIRT3 and PGC-1α in a Rat Model of Isoproterenol-Induced Cardiomyopathy

SARS-CoV-2 and mitochondrial health: implications of lifestyle and ageing

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