Adipocytes, aldosterone and obesity-related hypertension

Understanding the mechanisms linking obesity with hypertension is important in the current obesity epidemic as it may improve therapeutic interventions. Plasma aldosterone levels are positively correlated with body mass index and weight loss in obese patients is reported to be accompanied by decreased aldosterone levels. This suggests a relationship between adipose tissue and the production/secretion of aldosterone. Aldosterone is synthesized principally by the adrenal glands, but its production may be regulated by many factors, including factors secreted by adipocytes. In addition, studies have reported local synthesis of aldosterone in extra-adrenal tissues, including adipose tissue. Experimental studies have highlighted a role for adipocyte-secreted aldosterone in the pathogenesis of obesity-related cardiovascular complications via the mineralocorticoid receptor. This review focuses on how aldosterone secretion may be influenced by adipose tissue and the importance of these mechanisms in the context of obesity-related hypertension

The Role of Mitochondrial Uncoupling in the Development of Diabetic Nephropathy

Diabetes is closely associated with increased oxidative stress, especially originating from the mitochondria. A mechanism to reduce increased mitochondria superoxide production is to reduce the mitochondria membrane potential by releasing protons across the mitochondria membrane. This phenomenon is referred to as mitochondria uncoupling since oxygen is consumed independently of ATP being produced and can be mediated by Uncoupling Proteins (UCPs). However, increased oxygen consumption is potentially detrimental for the kidney since it can cause tissue hypoxia. Therefore, this thesis aimed to investigate the role of mitochondria uncoupling for development of diabetic nephropathy.      UCP-2 was demonstrated to be the only isoform expressed in the kidney, and localized to tubular segments performing the majority of tubular electrolyte transport. Streptozotocin-induced diabetes in rats increased UCP-2 protein expression and correlated to increased non-transport dependent oxygen consumption in isolated proximal tubular cells. These effects were prevented by intense insulin treatment to the diabetic animals demonstrating a pivotal role of hyperglycemia. Importantly, elevated UCP-2 protein expression increased mitochondria uncoupling in mitochondria isolated from diabetic kidneys. Mitochondria uncoupling and altered morphology was also evident in kidneys from db/db-mice, a model of type-2 diabetes, together with proteinuria and glomerular hyperfiltration which are both clinical manifestations of diabetic nephropathy. Treatment with the antioxidant coenzyme Q10 prevented mitochondria uncoupling as well as morphological and functional alterations in these kidneys. Acute knockdown of UCP-2 paradoxically increased mitochondria uncoupling in a mechanism involving the adenosine nucleotide transporter. Increased uncoupling via adenosine nucleotide transporter decreased mitochondria membrane potential and kidney oxidative stress but did not affect glomerular filtration rate, renal blood flow, total kidney oxygen consumption or intrarenal tissue oxygen tension.      The role of increased mitochondria oxygen consumption was investigated by administering the chemical uncoupler dinitrophenol to healthy rats. Importantly, increased mitochondria oxygen consumption resulted in kidney tissue hypoxia, proteinuria and increased staining of the tubular injury marker vimentin, demonstrating a crucial role of increased oxygen consumption per se and the resulting kidney tissue hypoxia for the development of nephropathy.      Taken together, the data presented in this thesis establishes an important role of mitochondria uncoupling for the development of diabetic nephropathy

Brown adipose tissue regulates small artery function through NADPH oxidase 4-derived hydrogen peroxide and redox-sensitive protein kinase G-1α

Objective—Biomedical interest in brown adipose tissue (BAT) has increased since the discovery of functionally active BAT in adult humans. Although white adipose tissue (WAT) influences vascular function, vascular effects of BAT are elusive. Thus, we investigated the regulatory role and putative vasoprotective effects of BAT, focusing on hydrogen peroxide, nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4), and redox-sensitive signaling. Approach and Results—Vascular reactivity was assessed in wild-type and Nox4-knockout mice (Nox4−/−) by wire myography in the absence and presence of perivascular adipose tissue of different phenotypes from various adipose depots: (1) mixed WAT/BAT (inguinal adipose tissue) and (2) WAT (epididymal visceral fat) and BAT (intrascapular fat). In wild-type mice, epididymal visceral fat and perivascular adipose tissue increased EC50 to noradrenaline without affecting maximum contraction. BAT increased EC50 and significantly decreased maximum contraction, which were prevented by a hydrogen peroxide scavenger (polyethylene glycated catalase) and a specific cyclic GMP–dependent protein kinase G type-1α inhibitor (DT-3), but not by inhibition of endothelial nitric oxide synthase or guanylate cyclase. BAT induced dimerization of cyclic GMP–dependent protein kinase G type-1α and reduced phosphorylation of myosin light chain phosphatase subunit 1 and myosin light chain 20. BAT from Nox4-knockout mice displayed reduced hydrogen peroxide levels and no anticontractile effects. Perivascular adipose tissue from β3 agonist–treated mice displayed browned perivascular adipose tissue and an increased anticontractile effect. Conclusions—We identify a novel vasoprotective action of BAT through an anticontractile effect that is mechanistically different to WAT. Specifically, BAT, via Nox4-derived hydrogen peroxide, induces cyclic GMP–dependent protein kinase G type-1α activation, resulting in reduced vascular contractility. BAT may constitute an interesting therapeutic target to restore vascular function and prevent vascular complications in cardiovascular diseases

Mitochondrial Reactive Oxygen Species and Kidney Hypoxia in the Development of Diabetic Nephropathy

The underlying mechanisms in the development of diabetic nephropathy are currently unclear and likely consist of a series of dynamic events from the early to late stages of the disease. Diabetic nephropathy is currently without curative treatments and it is acknowledged that even the earliest clinical manifestation of nephropathy is preceded by an established morphological renal injury that is in turn preceded by functional and metabolic alterations. An early manifestation of the diabetic kidney is the development of kidney hypoxia that has been acknowledged as a common pathway to nephropathy. There have been reports of altered mitochondrial function in the diabetic kidney such as altered mitophagy, mitochondrial dynamics, uncoupling, and cellular signaling through hypoxia inducible factors and AMP-kinase. These factors are also likely to be intertwined in a complex manner. In this review, we discuss how these pathways are connected to mitochondrial production of reactive oxygen species (ROS) and how they may relate to the development of kidney hypoxia in diabetic nephropathy. From available literature, it is evident that early correction and/or prevention of mitochondrial dysfunction may be pivotal in the prevention and treatment of diabetic nephropathy

Mitochondrial oxidative stress in obesity: role of the mineralocorticoid receptor

International audienceObesity is a multifaceted, chronic, low-grade inflammation disease characterized by excess accumulation of dysfunctional adipose tissue. It is often associated with the development of cardiovascular (CV) disorders, insulin resistance and diabetes. Under pathological conditions like in obesity, adipose tissue secretes bioactive molecules called 'adipokines', including cytokines, hormones and reactive oxygen species (ROS). There is evidence suggesting that oxidative stress, in particular, the ROS imbalance in adipose tissue, may be the mechanistic link between obesity and its associated CV and metabolic complications. Mitochondria in adipose tissue are an important source of ROS and their dysfunction contributes to the pathogenesis of obesity-related type 2 diabetes. Mitochondrial function is regulated by several factors in order to preserve mitochondria integrity and dynamics. Moreover, the renin-angiotensin-aldosterone system is over-activated in obesity. In this review, we focus on the pathophysiological role of the mineralocorticoid receptor in the adipose tissue and its contribution to obesity-associated metabolic and CV complications. More specifically, we discuss whether dysregulation of the mineralocorticoid system within the adipose tissue may be the upstream mechanism and one of the early events in the development of obesity, via induction of oxidative stress and mitochondrial dysfunction, thus impacting on systemic metabolism and the CV system

http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-79354 Acute Knockdown of Uncoupling Protein-2 Increases Uncoupling via the Adenine Nucleotide Transporter and Decreases Oxidative Stress in Diabetic Kidneys

Increased O2 metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O2 consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocininduced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expressio

Renal transplantation induces mitochondrial uncoupling, increased kidney oxygen consumption, and decreased kidney oxygen tension

Hypoxia is an acknowledged pathway to renal injury and ischemia-reperfusion (I/R) and is known to reduce renal oxygen tension (PO2). We hypothesized that renal I/R increases oxidative damage and induces mitochondrial uncoupling, resulting in increased oxygen consumption and hence kidney hypoxia. Lewis rats underwent syngenic renal transplantation (TX) and contralateral nephrectomy. Controls were uninephrectomized (1K-CON) or left untreated (2K-CON). After 7 days, urinary excretion of protein and thiobarbituric acid-reactive substances were measured, and after 14 days glomerular filtration rate (GFR), renal blood flow, whole kidney QO2, cortical PO2, kidney cortex mitochondrial uncoupling, renal oxidative damage, and tubulointerstitial injury were assessed. TX, compared with 1K-CON, resulted in mitochondrial uncoupling mediated via uncoupling protein-2 (16 ± 3.3 vs. 0.9 ± 0.4 pmol O2•s−1•mg protein−1, P 2 (55 ± 16 vs. 33 ± 10 μmol O2/min, P 2 was lower in TX compared with 1K-CON (30 ± 13 vs. 47 ± 4 μM, P 2, PO2, or injury. Collectively, our results demonstrate increased mitochondrial uncoupling as an early event after experimental renal transplantation associated with increased oxygen consumption and kidney hypoxia in the absence of increases in markers of damage

Thyroid hormone increases oxygen metabolism causing intrarenal tissue hypoxia; a pathway to kidney disease

The proposed mechanisms for the development of nephropathy are many, complex and often overlapping. Although recent literature strongly supports a role of kidney hypoxia as an independent pathway to nephropathy, the evidence remains inconclusive since the role of hypoxia is difficult to differentiate from confounding factors such as hyperglycemia, hypertension and oxidative stress. By increasing kidney oxygen consumption using triiodothyronine (T-3) and, thus, avoiding these confounding factors, the aim of the present study was to investigate renal hypoxia per se as a causal pathway for the development of nephropathy. Healthy Sprague-Dawley rats were treated with T-3 (10 mu g/kg/day) and the angiotensin II AT(1)-receptor antagonist candesartan (1 mg/kg in drinking water) to eliminate effects of T-3-induced renin release; and compared to a candesartan treated control group. After 7 weeks of treatment in vivo kidney function, oxygen metabolism and mitochondrial function were evaluated. T-3 did not affect glomerular filtration rate or renal blood flow, but increased total kidney oxygen consumption resulting in cortical hypoxia. Nephropathy, demonstrated as albuminuria and tubulointerstitial fibrosis, developed in T-3-treated animals. Mitochondria uncoupling mediated by uncoupling protein 2 and the adenosine nucleotide transporter was demonstrated as a mechanism causing the increased kidney oxygen consumption. Importantly, blood glucose levels, mean arterial blood pressure and oxidative stress levels were not affected by T-3. In conclusion, the present study provides further evidence for increased kidney oxygen consumption causing intrarenal tissue hypoxia, as a causal pathway for development of nephropathy

Dose-dependent regulation of kidney mitochondrial function by angiotensin II

Background: Intrarenal hypoxia has been suggested a unifying pathway to chronic kidney disease (CKD) and increased mitochondria leak respiration, which increases mitochondrial oxygen usage and is one important mechanism contributing to the development of the hypoxia. Previous studies indicate that angiotensin II (Ang II) effects on mitochondria function could be dose dependent. We investigated how moderate and high levels of Ang II affect kidney mitochondria function and pathways of leak respiration. Methods: C57 black 6 mice were treated with either vehicle or Ang II in low dose (400 ng/kg/min) or high dose (1,000 ng/kg/min) for 4 weeks. The function of kidney cortex mitochondria was measured by high-resolution respirometry. Ang II effects on gene expression in kidney tissue were measured by quantitative real-time PCR. Thiobarbituric acids reactive substances were determined as a marker of oxidative stress, and urinary protein excretion was measured as a maker of kidney injury. Results: Low-dose Ang II induced overall mitochondria respiration, without compromising capacity of ATP production. Mitochondrial leak respiration was increased, and levels of oxidative stress were unchanged. However, high-dose Ang II decreased overall mitochondria respiration and reduced mitochondrial capacity for ATP production. Mitochondrial leak respiration was decreased, and oxidative stress increased in kidney tissue. Furthermore, gene expression of mediators that stimulate vasoconstriction and ROS production was increased, while components of counteracting pathways were decreased. Conclusions: In conclusion, Ang II dose-dependently affects mitochondrial function and leak respiration. Thus, Ang II has the potential to directly affect cellular metabolism during conditions of altered Ang II signaling

Adipocyte-Mineralocorticoid Receptor Alters Mitochondrial Quality Control Leading to Mitochondrial Dysfunction and Senescence of Visceral Adipose Tissue

Mineralocorticoid receptor (MR) expression is increased in the adipose tissue (AT) of obese patients and animals. We previously demonstrated that adipocyte-MR overexpression in mice (Adipo-MROE mice) is associated with metabolic alterations. Moreover, we showed that MR regulates mitochondrial dysfunction and cellular senescence in the visceral AT of obese db/db mice. Our hypothesis is that adipocyte-MR overactivation triggers mitochondrial dysfunction and cellular senescence, through increased mitochondrial oxidative stress (OS). Using the Adipo-MROE mice with conditional adipocyte-MR expression, we evaluated the specific effects of adipocyte-MR on global and mitochondrial OS, as well as on OS-induced damage. Mitochondrial function was assessed by high throughput respirometry. Molecular mechanisms were probed in AT focusing on mitochondrial quality control and senescence markers. Adipo-MROE mice exhibited increased mitochondrial OS and altered mitochondrial respiration, associated with reduced biogenesis and increased fission. This was associated with OS-induced DNA-damage and AT premature senescence. In conclusion, targeted adipocyte-MR overexpression leads to an imbalance in mitochondrial dynamics and regeneration, to mitochondrial dysfunction and to ageing in visceral AT. These data bring new insights into the MR-dependent AT dysfunction in obesity