Low Aerobic Capacity and High-Fat Diet Contribute to Oxidative Stress and IRS-1 Degradation in the Kidney

Morris, E. Matthew; Whaley‐Connell, Adam; Thyfault, John P.; Britton, Steven L.; Koch, Lauren G.; Wei, Yongzhong; Ibdah, Jamal A.; Sowers, James R.

doi:10.1159/000204362

Cited by 18 publications

(13 citation statements)

References 73 publications

(59 reference statements)

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“…1,024 × 1,024 pixel images were captured with LSM imaging system under the same microscope and computer settings for all animals of four groups in each experiment. The signal intensities were measured and analyzed in the equal regions with MetaView as previously described [20,21,22,23,24]. …”

Section: Methodsmentioning

confidence: 99%

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Nebivolol Reduces Proteinuria and Renal NADPH Oxidase-Generated Reactive Oxygen Species in the Transgenic Ren2 Rat

Whaley‐Connell

Habibi²,

Johnson³

et al. 2009

Am J Nephrol

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Background/Aims: Renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system activation are crucial in the pathogenesis of hypertension, cardiovascular and renal disease. NADPH oxidase-mediated increases in reactive oxygen species (ROS) are an important mediator for RAAS-induced cardiovascular and renal injury. Increased levels of ROS can diminish the bioactivity of nitric oxide (NO), a critical modulator of RAAS effects on the kidney. Thereby, we hypothesized that in vivo nebivolol therapy in a rodent model of activated RAAS would attenuate glomerular damage and proteinuria through its actions to reduce NADPH oxidase activity/ROS and increase bioavailable NO. Methods: We utilized the transgenic Ren2 rat which displays heightened tissue RAAS, hypertension, and proteinuria. Ren2 rats (6–9 weeks of age) and age-matched Sprague-Dawley littermates were treated with nebivolol 10 mg/kg/day (osmotic mini-pump) for 21 days. Results: Ren2 rats exhibited increases in systolic blood pressure, proteinuria, kidney cortical tissue total NADPH oxidase activity and subunits (Rac1, p67^phox, and p47^phox), ROS and 3-nitrotyrosine, as well as reductions in podocyte protein markers; each of these parameters improved with nebivolol treatment along with increases in renal endothelial NO synthase expression. Conclusions: Our data suggest that nebivolol improves proteinuria through reductions in renal RAAS-mediated increases in NADPH oxidase/ROS and increases in bioavailable NO.

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Section: Methodsmentioning

confidence: 99%

“…Thiswas measured by chemiluminescence as previously described [23]. Briefly, kidney tissue sections were homogenized in sucrose buffer using a glass/glass homogenizer, centrifuged, and supernatants (whole homogenate) were then removed and placed on ice.…”

Section: Methodsmentioning

confidence: 99%

Nebivolol Reduces Proteinuria and Renal NADPH Oxidase-Generated Reactive Oxygen Species in the Transgenic Ren2 Rat

Whaley‐Connell

Habibi²,

Johnson³

et al. 2009

Am J Nephrol

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“…Overnutrition (especially that characterized by excess intake of fat and carbohydrates) is a major factor in the increased prevalence of hypertension, CRS, and diabetes. These co-morbidities may be driven by decreases in INS-mediated vascular relaxation, and glucose transport in cardiovascular (CV) and skeletal muscle tissue [1,2,3,4,5,6,7]. In addition to overnutrition, several other mechanisms, such as enhanced activation of the renin-angiotensin-aldosterone system (RAAS), inflammation, and associated abnormalities in INS metabolic signaling, may help explain the linkage between INS resistance, hypertension and the CRS [8,9,10,11,12,13,14,15].…”

Section: Introductionmentioning

confidence: 99%

The Impact of Overnutrition on Insulin Metabolic Signaling in the Heart and the Kidney

Pulakat¹,

DeMarco²,

Whaley‐Connell³

et al. 2011

Cardiorenal Med

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Overnutrition characterized by overconsumption of food rich in fat and carbohydrates is a significant contributor to hypertension, type 2 diabetes, and the cardiorenal syndrome. Overnutrition activates the renin-angiotensin-aldosterone system (RAAS) and causes chronic exposure of cardiovascular and renal tissue to increased circulating nutrients, insulin (INS), and angiotensin II (ANG II). Emerging evidence suggests that overnutrition, aldosterone, and ANG II promote INS resistance, a chronic condition that underlies these co-morbidities, through activation of the mammalian target of the rapamycin (mTOR)/S6 kinase 1 (S6K1) signaling pathway in cardiovascular tissue and the kidney. However, a novel ANG II type 2 receptor (AT₂R)-mediated cross talk between the RAAS and mTOR pathways ameliorates overnutrition-induced activation of mTOR/S6K1 signaling in cardiovascular tissue of rats, mice, and humans and confers cardioprotection.

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“…LCR rats also exhibited reduced hepatic mitochondrial oxidative capacity and steatosis (45). Moreover, high-fat diets increased the risks for the development of cardiovascular, metabolic, and renal abnormalities in LCR rats (4,35). Thus, LCR rats exhibit metabolic and cardiovascular phenotypes (i.e., overweight, insulin resistance, elevated blood pressure, and dyslipidemia).…”

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Overweight female rats selectively breed for low aerobic capacity exhibit increased myocardial fibrosis and diastolic dysfunction

DeMarco

Johnson

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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The statistical association between endurance exercise capacity and cardiovascular disease suggests that impaired aerobic metabolism underlies the cardiovascular disease risk in men and women. To explore this connection, we applied divergent artificial selection in rats to develop low-capacity runner (LCR) and high-capacity runner (HCR) rats and found that disease risks segregated strongly with low running capacity. Here, we tested if inborn low aerobic capacity promotes differential sex-related cardiovascular effects. Compared with HCR males (HCR-M), LCR males (LCR-M) were overweight by 34% and had heavier retroperitoneal, epididymal, and omental fat pads; LCR females (LCR-F) were 20% heavier than HCR females (HCR-F), and their retroperitoneal, but not perireproductive or omental, fat pads were heavier as well. Unlike HCR-M, blood pressure was elevated in LCR-M, and this was accompanied by left ventricular (LV) hypertrophy. Like HCR-F, LCR-F exhibited normal blood pressure and LV weight as well as increased spontaneous cage activity compared with males. Despite normal blood pressures, LCR-F exhibited increased myocardial interstitial fibrosis and diastolic dysfunction, as indicated by increased LV stiffness, a decrease in the initial filling rate, and an increase in diastolic relaxation time. Although females exhibited increased arterial stiffness, ejection fraction was normal. Increased interstitial fibrosis and diastolic dysfunction in LCR-F was accompanied by the lowest protein levels of phosphorylated AMP-actived protein kinase [phospho-AMPK (Thr(172))] and silent information regulator 1. Thus, the combination of risk factors, including female sex, intrinsic low aerobic capacity, and overweightness, promote myocardial stiffness/fibrosis sufficient to induce diastolic dysfunction in the absence of hypertension and LV hypertrophy.

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Low Aerobic Capacity and High-Fat Diet Contribute to Oxidative Stress and IRS-1 Degradation in the Kidney

Cited by 18 publications

References 73 publications

Nebivolol Reduces Proteinuria and Renal NADPH Oxidase-Generated Reactive Oxygen Species in the Transgenic Ren2 Rat

Nebivolol Reduces Proteinuria and Renal NADPH Oxidase-Generated Reactive Oxygen Species in the Transgenic Ren2 Rat

The Impact of Overnutrition on Insulin Metabolic Signaling in the Heart and the Kidney

Overweight female rats selectively breed for low aerobic capacity exhibit increased myocardial fibrosis and diastolic dysfunction

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