Modulation of mitochondria and NADPH oxidase function by the nitrate-nitrite-NO pathway in metabolic disease with focus on type 2 diabetes

Schiffer, Tomas A.; Lundberg, Jon O.; Weitzberg, Eddie; Carlström, Mattias

doi:10.1016/j.bbadis.2020.165811

Cited by 30 publications

(16 citation statements)

References 159 publications

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“…We have earlier shown that dietary nitrate improves mitochondrial efficiency in humans [ 46 ]. Stimulation of the nitrate-nitrite-NO pathway has in several recent experimental studies been associated with favorable effects on mitochondrial function during metabolic disorders, including type 2 diabetes, via mechanisms that involve dampening of oxidative stress [ 47 ]. Moreover, Shiva and colleagues have demonstrated that both pre- and acute treatment with inorganic nitrite has cytoprotective effects and potentially limits cardiac and hepatic reperfusion injury via modulation of mitochondria electron transport chain and reduction of ROS [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

“…Increased Ang II signaling is widely known to stimulate NADPH oxidase and mitochondria-derived ROS production, leading to oxidative stress [ [49] , [50] , [51] ]. Cao and colleagues showed that a reno-cerebral reflex activated the renin-angiotensin system following IR, which promoted oxidative stress and progression of renal injuries [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

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Renovascular effects of inorganic nitrate following ischemia-reperfusion of the kidney

et al. 2021

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Background Renal ischemia-reperfusion (IR) injury is a common cause of acute kidney injury (AKI), which is associated with oxidative stress and reduced nitric oxide (NO) bioactivity and increased risk of developing chronic kidney disease (CKD) and cardiovascular disease (CVD). New strategies that restore redox balance may have therapeutic implications during AKI and associated complications. Aim To investigate the therapeutic value of boosting the nitrate-nitrite-NO pathway during development of IR-induced renal and cardiovascular dysfunction. Methods Male C57BL/6 J mice were given sodium nitrate (10 mg/kg, i. p) or vehicle 2 h prior to warm ischemia of the left kidney (45 min) followed by sodium nitrate supplementation in the drinking water (1 mmol/kg/day) for the following 2 weeks. Blood pressure and glomerular filtration rate were measured and blood and kidneys were collected and used for biochemical and histological analyses as well as renal vessel reactivity studies. Glomerular endothelial cells exposed to hypoxia-reoxygenation, with or without angiotensin II, were used for mechanistic studies. Results IR was associated with reduced renal function and slightly elevated blood pressure, in combination with renal injuries, inflammation, endothelial dysfunction, increased Ang II levels and Ang II-mediated vasoreactivity, which were all ameliorated by nitrate. Moreover, treatment with nitrate (in vivo) and nitrite (in vitro) restored NO bioactivity and reduced mitochondrial oxidative stress and injuries. Conclusions Acute treatment with inorganic nitrate prior to renal ischemia may serve as a novel therapeutic approach to prevent AKI and CKD and associated risk of developing cardiovascular dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Renovascular effects of inorganic nitrate following ischemia-reperfusion of the kidney

et al. 2021

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“…The effect of NO on tubular reabsorption could potentially be concentration dependent and involve interaction with regulatory hormonal systems such as the RAAS. Although the effects of NO on proximal tubular reabsorption is debated, NO clearly has an important role in kidney physiology and compromised NO bioactivity is associated with kidney disease and associated cardiovascular and metabolic disorders 7 , 38 , 39 .…”

Section: Modulation Of Sodium Transport By Nomentioning

confidence: 99%

“…Almost a decade ago, supplementation with dietary doses of nitrate was demonstrated to reverse features of metabolic syndrome in mice that lacked eNOS 180 . Numerous experimental studies have since confirmed that nitrate supplementation has favourable metabolic effects, which involve modulation of mitochondrial function and oxidative stress, activation of AMP-activated protein kinase (AMPK) signalling and modulation of downstream targets including sterol regulatory element-binding protein 1, acetyl-CoA carboxylase, medium-chain specific acyl-CoA dehydrogenase, mitochondrial and peroxisome proliferator-activated receptor-γ coactivator 1α 7 , 181 – 184 . A link between nitrate and/or nitrite supplementation and AMPK activation has also been demonstrated in experimental models of heart failure with preserved ejection fraction 182 and IRI of the heart 185 as well as in studies of the potential beneficial effects of this supplementation on longevity 186 .…”

Section: Approaches To Restoring No Bioactivitymentioning

confidence: 99%

“…Potential mechanisms that might contribute to the development of kidney disease, cardiovascular disease and T2DM include hyperglycaemia, altered lipid metabolism, low-grade inflammation, overactivity of the renin–angiotensin–aldosterone system (RAAS), increased sympathetic nerve activity and altered microbiota 3 – 6 . In addition, several studies have suggested a substantial contribution of increased generation of NADPH oxidase-derived and mitochondria-derived reactive oxygen species (ROS) and oxidative stress coupled with reduced nitric oxide (NO) bioactivity and endothelial dysfunction 7 – 10 . NO is a short-lived diatomic signalling molecule that exerts multiple effects on kidney, cardiovascular and metabolic functions, including modulation of renal autoregulation, tubular fluid and electrolyte transport, vascular tone, blood pressure, platelet aggregation, immune cell activation, insulin-glucose homeostasis and mitochondrial function.…”

Section: Introductionmentioning

confidence: 99%

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Nitric oxide signalling in kidney regulation and cardiometabolic health

Carlström

2021

Nat Rev Nephrol

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The prevalence of cardiovascular and metabolic disease coupled with kidney dysfunction is increasing worldwide. This triad of disorders is associated with considerable morbidity and mortality as well as a substantial economic burden. Further understanding of the underlying pathophysiological mechanisms is important to develop novel preventive or therapeutic approaches. Among the proposed mechanisms, compromised nitric oxide (NO) bioactivity associated with oxidative stress is considered to be important. NO is a short-lived diatomic signalling molecule that exerts numerous effects on the kidneys, heart and vasculature as well as on peripheral metabolically active organs. The enzymatic l -arginine-dependent NO synthase (NOS) pathway is classically viewed as the main source of endogenous NO formation. However, the function of the NOS system is often compromised in various pathologies including kidney, cardiovascular and metabolic diseases. An alternative pathway, the nitrate–nitrite–NO pathway, enables endogenous or dietary-derived inorganic nitrate and nitrite to be recycled via serial reduction to form bioactive nitrogen species, including NO, independent of the NOS system. Signalling via these nitrogen species is linked with cGMP-dependent and independent mechanisms. Novel approaches to restoring NO homeostasis during NOS deficiency and oxidative stress have potential therapeutic applications in kidney, cardiovascular and metabolic disorders.

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