Obesity and Kidney Disease

Lakkis, Jay I.; Mr, Weir

doi:10.1016/j.pcad.2018.07.005

Cited by 127 publications

(108 citation statements)

References 149 publications

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“…The most common causes of inflammatory-metabolic HFpEF -diabetes and obesity -are important causes of chronic kidney disease. 77 Additionally, other diseases that are linked to HFpEF (e.g. rheumatoid arthritis, psoriasis and non-alcoholic steatohepatitis) increase the risk of chronic kidney disease, in proportion to the severity of the inflammatory derangement.…”

Section: Metabolic and Hormonal Derangements Leading To Heart Failurementioning

confidence: 99%

Characterization of the inflammatory‐metabolic phenotype of heart failure with a preserved ejection fraction: a hypothesis to explain influence of sex on the evolution and potential treatment of the disease

Packer

Lam

Lund

et al. 2020

European J of Heart Fail

112

109

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Accumulating evidence points to the existence of an inflammatory-metabolic phenotype of heart failure with a preserved ejection fraction (HFpEF), which is characterized by biomarkers of inflammation, an expanded epicardial adipose tissue mass, microvascular endothelial dysfunction, normal-to-mildly increased left ventricular volumes and systolic blood pressures, and possibly, altered activity of adipocyte-associated inflammatory mediators. A broad range of adipogenic metabolic and systemic inflammatory disorders-e.g. obesity, diabetes and metabolic syndrome as well as rheumatoid arthritis and psoriasis-can cause this phenotype, independent of the presence of large vessel coronary artery disease. Interestingly, when compared with men, women are both at greater risk of and may suffer greater cardiac consequences from these systemic inflammatory and metabolic disorders. Women show disproportionate increases in left ventricular filling pressures following increases in central blood volume and have greater arterial stiffness than men. Additionally, they are particularly predisposed to epicardial and intramyocardial fat expansion and imbalances in adipocyte-associated proinflammatory mediators. The hormonal interrelationships seen in inflammatory-metabolic phenotype may explain why mineralocorticoid receptor antagonists and neprilysin inhibitors may be more effective in women than in men with HFpEF. Recognition of the inflammatory-metabolic phenotype may improve an understanding of the pathogenesis of HFpEF and enhance the ability to design clinical trials of interventions in this heterogeneous syndrome.

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Section: Metabolic and Hormonal Derangements Leading To Heart Failurementioning

confidence: 99%

Characterization of the inflammatory‐metabolic phenotype of heart failure with a preserved ejection fraction: a hypothesis to explain influence of sex on the evolution and potential treatment of the disease

Packer

Lam

Lund

et al. 2020

European J of Heart Fail

112

109

View full text Add to dashboard Cite

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“…This signaling cascade evidently produces further ROS and causes a decline in the overall cellular defensive mechanisms that scavenges ROS, further aggravating the cellular pro-oxidant state. We have specifically shown that this pathway is critical to the pathophysiology of several experimental models of disease including obesity and metabolic syndrome [ 17 , 21 ]. In this regard, our peptide, pNaKtide, has been recently reported to attenuate oxidant stress by the antagonism of Na/K-ATPase signaling [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Uremic Toxins Activates Na/K-ATPase Oxidant Amplification Loop Causing Phenotypic Changes in Adipocytes in In Vitro Models

Bartlett

Miller

Thiesfeldt

et al. 2018

IJMS

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Background: Oxidant stress plays a key role in the development of chronic kidney disease (CKD). Experimental CKD leads to accumulation of uremic toxins (UT) in the circulation resulting in increased ROS production, which in turn, is known to activate the Na/K-ATPase/ROS amplification loop. Studies in a murine model of obesity have shown that increased oxidative stress in plasma is due to increased ROS and cytokine production from dysfunctional adipocytes. Therefore, we hypothesized that adipocytes exposed to UTs will activate the Na/K-ATPase oxidant amplification loop causing redox imbalance and phenotypic alterations in adipocytes. We also aimed to demonstrate that the Na/K-ATPase signaling antagonist, pNaKtide, attenuates these pathophysiological consequences. Methods: In the first set of experiments, 3T3-L1 murine pre-adipocytes were treated with varying concentrations of UTs, indoxyl sulfate (IS) (50, 100 and 250 µM) and p-cresol (50, 100 and 200 µM), with or without pNaKtide (0.7 µM) for five days in adipogenic media, followed by Oil Red O staining to study adipogenesis. RT-PCR analysis was performed to study expression of adipogenic, apoptotic and inflammatory markers, while DHE staining evaluated the superoxide levels in UT treated cells. In a second set of experiments, visceral fat was obtained from the West Virginian population. MSCs were isolated and cultured in adipogenic media for 14 days, which was treated with indoxyl sulfate (0, 25, 50 and 100 µM) with or without pNaKtide (1 µM). MSC-derived adipocytes were evaluated for morphological and molecular analysis of the above markers. Results: Our results demonstrated that 3T3-L1 cells and MSCs-derived adipocytes, treated with UTs, exhibited a significant decrease in adipogenesis and apoptosis through activation of the Na/K-ATPase/ROS amplification loop. The treatment with pNaKtide in 3T3-L1 cells and MSC-derived adipocytes negated the effects of UTs and restored cellular redox in adipocytes. We noted a varying effect of pNaKtide, in adipocytes treated with UTs, on inflammatory markers, adipogenic marker and superoxide levels in 3T3-L1 cells and MSC-derived adipocytes. Conclusions: This study demonstrates for the first time that the Na/K-ATPase/ROS amplification loop activated by elevated levels of UTs has varying effect on phenotypic alterations in adipocytes in various in vitro models. Thus, we propose that, if proven in humans, inhibition of Na/K-ATPase amplification of oxidant stress in CKD patients may ultimately be a novel way to combat adipocyte dysfunction and metabolic imbalance in these patients.

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“…Additionally, obesity is associated with more baseline restrictive pulmonary disease and hypoventilation, as well as low-grade systemic inflammation [15,16]. Adding to this pulmonary insufficiency is the fact that low cardiorespiratory fitness is often present in obesity and, along with adiposity, is a major risk factor for the development of HF, especially HFpEF, thus leading to an increased risk of pulmonary vascular congestion due to HF in obesity, especially in more severe forms of obesity [7,14,17].…”

mentioning

confidence: 99%

“…COVID-19 is also often accompanied by a multisystem disease, and individuals with overweight and obesity at baseline have an increased prevalence of renal insufficiency and chronic kidney disease, leading to these patients having less renal reserve [15]. Besides having more CVDs, especially HF [7,14,17], patients with obesity also are particularly vulnerable to develop AF [16], which appears to be an additional risk factor in COVID-19.…”

mentioning

confidence: 99%