Moderate hyperbilirubinemia improves renal hemodynamics in ANG II-dependent hypertension

Vera, Trinity; Stec, David E.

doi:10.1152/ajpregu.00316.2010

Cited by 40 publications

(40 citation statements)

References 37 publications

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“…[83][84][85] Recent studies have shown that the antioxidant effects of mildly elevated serum bilirubin levels may protect against diseases that are associated with oxidative stress 86 through mechanisms that decrease oxidative stress and increase NO levels. 87,88 A mild increase within the physiological range of serum bilirubin concentration is negatively correlated with hypertension. 89 Finally, uric acid has long been recognized for its antioxidant properties and is the most abundant scavenger of free radicals in humans.…”

Section: Endogenous Antioxidantsmentioning

confidence: 99%

The role of oxidative stress in the pathophysiology of hypertension

2011

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Hypertension is considered to be the most important risk factor in the development of cardiovascular disease. An increasing body of evidence suggests that oxidative stress, which results in an excessive generation of reactive oxygen species (ROS), has a key role in the pathogenesis of hypertension. The modulation of the vasomotor system involves ROS as mediators of vasoconstriction induced by angiotensin II, endothelin-1 and urotensin-II, among others. The bioavailability of nitric oxide (NO), which is a major vasodilator, is highly dependent on the redox status. Under physiological conditions, low concentrations of intracellular ROS have an important role in the normal redox signaling maintaining vascular function and integrity. However, under pathophysiological conditions, increased levels of ROS contribute to vascular dysfunction and remodeling through oxidative damage. In human hypertension, an increase in the production of superoxide anions and hydrogen peroxide, a decrease in NO synthesis and a reduction in antioxidant bioavailability have been observed. In turn, antioxidants are reducing agents that can neutralize these oxidative and otherwise damaging biomolecules. The use of antioxidant vitamins, such as vitamins C and E, has gained considerable interest as protecting agents against vascular endothelial damage. Available data support the role of these vitamins as effective antioxidants that can counteract ROS effects. This review discusses the mechanisms involved in ROS generation, the role of oxidative stress in the pathogenesis of vascular damage in hypertension, and the possible therapeutic strategies that could prevent or treat this disorder. Hypertension Research (2011) 34, 431-440; doi:10.1038/hr.2010.264; published online 13 January 2011Keywords: antioxidants; endothelial dysfunction; oxidative stress INTRODUCTION Hypertension is considered the most important risk factor for the occurrence of cardiovascular disease. 1 Oxidative stress has gained attention as one of the fundamental mechanisms responsible for the development of hypertension. Reactive oxygen species (ROS) have an important role in the homeostasis of the vascular wall; hence, they could be part of the mechanism that leads to hypertension. 2-4 Thus, increased ROS production, reduced nitric oxide (NO) levels and reduced antioxidant bioavailability were demonstrated in experimental and human hypertension. Vascular superoxide is primarily derived from nicotinamide adenine dineucleotide phosphate (NADPH) oxidase when stimulated by hormones, such as angiotensin II (AT-II), endothelin-1 (ET-1) and urotensin II. In addition, increased ROS production may be generated by mechanical stimuli on the vascular wall, which increase with hypertension. ROS-induced vasoconstriction results from increased intracellular calcium concentration, thereby contributing to the pathogenesis of hypertension. 2 Vasomotor tone is dependent on a delicate balance between vasoconstrictor and vasodilator forces that result from the interaction between the components of...

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Section: Endogenous Antioxidantsmentioning

confidence: 99%

The role of oxidative stress in the pathophysiology of hypertension

2011

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“…Gunn rats are also resistant to angiotensin (ANG II)-induced hypertension (132,150,174,175). Systemic blood pressure in Gunn rats was reduced by 50% compared with controls after chronic ANG II administration.…”

Section: Potential Protective Effects Of Bilirubinmentioning

confidence: 99%

“…Indinavir administration or bilirubin infusion significantly lowered mean arterial pressure and increased plasma nitrate/nitrite concentrations after ANG II administration. Moderate hyperbilirubinemia also restores glomerular filtration rate (GFR) and renal blood flow in ANG II-dependent hypertensive mice (175). In addition, urinary protein excretion was significantly lower in bilirubintreated ANG II-infused rats (93 renoprotective effects in ANG II-treated animal models (150).…”

Section: Potential Protective Effects Of Bilirubinmentioning

confidence: 99%

Circulating bilirubin and defense against kidney disease and cardiovascular mortality: mechanisms contributing to protection in clinical investigations

Boon

Bulmer

Coombes

et al. 2014

American Journal of Physiology-Renal Physiology

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Unconjugated bilirubin is an endogenous circulating antioxidant, bound to albumin, and therefore is retained in the vascular compartment. Bilirubin has well-documented neurotoxic effects in infants; however, current evidence indicates mildly elevated bilirubin is associated with protection from cardiovascular disease and all-cause mortality in adults. Recent clinical studies show mildly elevated bilirubin is associated with protection from kidney damage and dysfunction, in addition to cardiovascular events and all-cause mortality in patients undergoing hemodialysis. This is the first review to examine the clinical evidence and summarize the potential mechanisms of action that link bilirubin to protection from kidney damage, subsequent kidney failure, and dialysis-related mortality. With this understanding, it is hoped that new therapies will be developed to prevent renal dysfunction and mortality from cardiovascular disease in at-risk individuals.

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“…26 Total bilirubin was measured using a Quantichrom Bilirubin Assay kit (BioAssay Systems, Hayward, CA, USA) according to the manufacturer's instructions. 28,29 Plasma iron was measured by flame atomic absorption. Blank reagent was processed in parallel and its iron content was subtracted from that of the samples to correct for background iron.…”

Section: Ischemic/reperfusion Protocolmentioning

confidence: 99%

Abnormal modulation of cell protective systems in response to ischemic/reperfusion injury is important in the development of mouse sickle cell hepatopathy

Siciliano¹,

Malpeli²,

Platt³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundSickle cell disease, a genetic red cell disorder inherited in an autosomal recessive manner, occurs throughout the world. Hepatic dysfunction and liver damage may be present in sickle cell disease, but the pathogenesis of these conditions is only partially understood. Design and MethodsTransgenic mice with sickle cell disease (SAD mice) and wild-type mice were exposed to an ischemic/reperfusion stress. The following parameters were evaluated: hematologic profile, transaminase and bilirubin levels, liver histopathology, and mRNA levels of nuclear factor-κB p65, endothelial nitric oxide synthase, inducible nitric oxide synthase, heme oxygenase-1 and phosphodiesterase-1, -2, -3, and -4 genes in hepatocytes obtained by laser-capture microdissection. Immunoblotting was used to analyze the expression of the following proteins: nuclear factor-κB p65 and phospho-nuclear factor-κB p65, heme oxygenase-1, biliverdin reductase, heat shock protein-70, heat shock protein-27 and peroxiredoxin-6. A subgroup of SAD mice was treated with the phosphodiesterase-4 inhibitor rolipram (30 mg/Kg/day by gavage) during the ischemic/reperfusion protocol. ResultsIn SAD mice the ischemic/reperfusion stress induced liver damage compatible with sickle cell disease hepatopathy, which was associated with: (i) lack of hypoxia-induced nuclear factor-κB p65 activation; (ii) imbalance in the endothelial/inducible nitric oxide synthase response to ischemic/reperfusion stress; (iii) lack of hypoxia-induced increased expression of heme oxygenase-1/biliverdin reductase paralleled by a compensatory increased expression of heat shock proteins 70 and 27 and peroxiredoxin-6; and (iv) up-regulation of the phosphodiesterase-1, -2, -3, and -4 genes. In SAD mice the phosphodiesterase-4 inhibitor rolipram attenuated the ischemic/reperfusion-related microcirculatory dysfunction, reduced the inflammatory cell infiltration and induced the heme oxygenase-1/ biliverdin reductase cytoprotective systems. ConclusionsIn SAD mice, sickle cell hepatopathy is associated with perturbed nuclear factor-κB p65 signaling with an imbalance of endothelial/inducible nitric oxide synthase levels, lack of heme oxygenase-1/biliverdin reductase expression and up-regulation of two novel cytoprotective systems: heat shock protein-27 and peroxiredoxin-6.Key words: NF-κB p65, endothelial nitric oxide synthase, inducible nitric oxide synthase, heat shock protein-70, heat shock protein-27, peroxiredoxin-6.

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Moderate hyperbilirubinemia improves renal hemodynamics in ANG II-dependent hypertension

Cited by 40 publications

References 37 publications

The role of oxidative stress in the pathophysiology of hypertension

The role of oxidative stress in the pathophysiology of hypertension

Circulating bilirubin and defense against kidney disease and cardiovascular mortality: mechanisms contributing to protection in clinical investigations

Abnormal modulation of cell protective systems in response to ischemic/reperfusion injury is important in the development of mouse sickle cell hepatopathy

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