Age-Related Mitochondrial Impairment and Renal Injury Is Ameliorated by Sulforaphane via Activation of Transcription Factor NRF2.

Age is one of the major risk factors for the development of chronic pathologies, including kidney diseases. Oxidative stress and mitochondrial dysfunction play a pathogenic role in aging kidney disease. Transcription factor NRF2, a master regulator of redox homeostasis, is altered during aging, but the exact implications of altered NRF2 signaling on age-related renal mitochondrial impairment are not yet clear.

Nrf2 inhibition induces oxidative stress, renal inflammation and hypertension in mice.

Oxidative stress and renal inflammation play a pivotal role in the pathogenesis of hypertension. The redox-sensitive transcription factor, nuclear factor E2-related factor 2 (Nrf2) is the master regulator of phase II antioxidant enzymes that protects against oxidative stress and inflammation. This study aimed to investigate the effect of Nrf2 inhibition on oxidative stress-associated hypertension and renal dopamine 1 receptor (D1R) dysfunction in mice.

Protein disulfide isomerase inhibition impairs Keap1/Nrf2 signaling and mitochondrial function and induces apoptosis in renal proximal tubular cells.

Renal proximal tubular apoptosis plays a critical role in kidney health and disease. However, cellular molecules that trigger renal apoptosis remain elusive. Here, we evaluated the effect of inhibiting protein disulfide isomerase (PDI), a critical thioredoxin chaperone protein, on apoptosis as well as the underlying mechanisms in human renal proximal tubular (HK2) cells.

Renal Dopamine Oxidation and Inflammation in High Salt Fed Rats.

Background Oxidative stress and high salt intake could be independent or intertwined risk factors in the origin of hypertension. Kidneys are the major organ to regulate sodium homeostasis and blood pressure and the renal dopamine system plays a pivotal role in sodium regulation during sodium replete conditions. Oxidative stress has been implicated in renal dopamine dysfunction and development of hypertension, especially in salt-sensitive animal models.

Kidney dopamine D-like receptors and angiotensin 1-7 interaction inhibits renal Na transporters.

The role of dopamine D-like receptors (DR) in the regulation of renal Na transporters, natriuresis, and blood pressure is well established. However, the involvement of the angiotensin 1-7 (ANG 1-7)-Mas receptor in the regulation of Na balance and blood pressure is not clear. The present study aimed to investigate the hypothesis that ANG 1-7 can regulate Na homeostasis by modulating the renal dopamine system.

Oxidative stress impairs cGMP-dependent protein kinase activation and vasodilator-stimulated phosphoprotein serine-phosphorylation.

Reactive oxygen species induce vascular dysfunction and hypertension by directly interacting with nitric oxide (NO) which leads to NO inactivation. In addition to a decrease in NO bioavailability, there is evidence that oxidative stress can also modulate NO signaling during hypertension. Here, we investigated the effect of oxidative stress on NO signaling molecules cGMP-dependent protein kinase (PKG) and vasodilator-stimulated phosphoprotein (VASP) which are known to mediate vasodilatory actions of NO.

Resveratrol restored Nrf2 function, reduced renal inflammation, and mitigated hypertension in spontaneously hypertensive rats.

Compelling evidence supports the role of oxidative stress and renal interstitial inflammation in the pathogenesis of hypertension. Resveratrol is a polyphenolic stilbene, which can lower oxidative stress by activating the transcription factor nuclear factor-E2-related factor-2 (Nrf2), the master regulator of numerous genes encoding antioxidant and phase II-detoxifying enzymes and molecules. Given the role of oxidative stress and inflammation in the pathogenesis of hypertension, we conducted this study to test the hypothesis that long-term administration of resveratrol will attenuate renal inflammation and oxidative stress and, hence, progression of hypertension in the young spontaneously hypertensive rats (SHR).

Transcriptional regulation of renal dopamine D1 receptor function during oxidative stress.

There exists a strong link between oxidative stress, renal dopaminergic system, and hypertension. It is reported that reactive oxygen species attenuate renal proximal tubular dopamine receptor (D1R) function, which disrupts sodium regulation and leads to hypertension. However, the mechanisms for renal D1R dysfunction are not clear.

Vascular oxidative stress upregulates angiotensin II type I receptors via mechanisms involving nuclear factor kappa B.

Abstract The association of oxidative stress with hypertension is well known. However, a causal role of oxidative stress in hypertension is unclear. Vascular angiotensin II type 1 receptor (AT1R) upregulation is a prominent contributor to pathogenesis of hypertension.

Transcription factor Nrf2 protects renal dopamine D1 receptor function during oxidative stress.

The renal dopaminergic system plays a significant role in controlling sodium excretion and blood pressure (BP). Overwhelming evidence shows that oxidative stress downregulates renal dopamine receptors (D1R), and antioxidant supplementation protects D1R function. However, the mechanisms for benefits of antioxidants in protecting D1R function are unknown.

Astrogliosis in the brain of obese Zucker rat: a model of metabolic syndrome.

Metabolic syndrome (MetS) is a disorder characterized primarily by the development of insulin resistance. Insulin resistance and subsequent hyperinsulinemia, originating from abdominal obesity, increases the risk of cerebrovascular and cardiovascular disease and all-cause mortality. Obesity is probably a risk factor for Alzheimer's disease and vascular dementia and is associated with impaired cognitive function.

Altered functioning of both renal dopamine D1 and angiotensin II type 1 receptors causes hypertension in old rats.

Activation of renal dopamine D1 (D1R) and angiotensin II type 1 receptors (AT(1)Rs) influences the activity of proximal tubular sodium transporter Na,K-ATPase and maintains sodium homeostasis and blood pressure. We reported recently that diminished D1R and exaggerated AT(1)R functions are associated with hypertension in old Fischer 344 × Brown Norway F1 (FBN) rats, and oxidative stress plays a central role in this phenomenon. Here we studied the mechanisms of age-associated increase in oxidative stress on diminished D1R and exaggerated AT(1)R functions in the renal proximal tubules of control and antioxidant Tempol-treated adult and old FBN rats.

Novel role of NF-κB-p65 in antioxidant homeostasis in human kidney-2 cells.

Nuclear factor-κB (NF-κB) plays a role in inflammation. However, we recently reported an association between NF-κB and antioxidant enzymes in renal proximal tubules of exercise-trained rats, suggesting its role in antioxidant homeostasis (George L, Lokhandwala MF, Asghar M. Am J Physiol Renal Physiol 297: F1174-F1180, 2009).

Defective nitric oxide production impairs angiotensin II-induced Na-K-ATPase regulation in spontaneously hypertensive rats.

Angiotensin (ANG) II via ANG II type 1 receptors (AT1R) activates renal sodium transporters including Na-K-ATPase and regulates sodium homeostasis and blood pressure. It is reported that at a high concentration, ANG II either inhibits or fails to stimulate Na-K-ATPase. However, the mechanisms for these phenomena are not clear.

Dopamine and vascular dynamics control: present status and future perspectives.

The catecholamine dopamine is a precursors in the biosynthesis of norepinephrine and epinephrine as well as a neurotransmitter in the central nervous system. Besides of its well known role of brain neurotransmitter, dopamine exerts specific functions at the periphery, being those at the level of the cardiovascular system and the kidney the most relevant. In fact it plays a role of modulator of blood pressure, sodium balance, and renal and adrenal functions through an independent peripheral dopaminergic system.

Resveratrol prevents endothelial nitric oxide synthase uncoupling and attenuates development of hypertension in spontaneously hypertensive rats.

Endothelial dysfunction is a hallmark of hypertension and vascular oxidative stress can contribute to endothelial dysfunction and hypertension development. Resveratrol is an antioxidant polyphenol which improves endothelium dependent relaxation, the mechanisms of which are unknown. Also, the role of resveratrol in hypertension remains to be established.

Potential dopamine-1 receptor stimulation in hypertension management.

The role of dopamine receptors in blood pressure regulation is well established. Genetic ablation of both dopamine D1-like receptor subtypes (D1, D5) and D2-like receptor subtypes (D2, D3, D4) results in a hypertensive phenotype in mice. This review focuses on the dopamine D1-like receptor subtypes D1 and D5 (especially D1 receptors), as they play a major role in regulating sodium homeostasis and blood pressure.

Angiotensin II-mediated biphasic regulation of proximal tubular Na+/H+ exchanger 3 is impaired during oxidative stress.

Angiotensin (ANG) II via AT1 receptors (AT1Rs) maintains sodium homeostasis by regulating renal sodium transporters including Na(+)/H(+) exchanger 3 (NHE3) in a biphasic manner. Low-ANG II concentration stimulates whereas high concentrations inhibit NHE3 activity. Oxidative stress has been shown to upregulate AT1R function that could modulate the ANG II-mediated NHE3 regulation.

Oxidative stress causes renal angiotensin II type 1 receptor upregulation, Na+/H+ exchanger 3 overstimulation, and hypertension.

Oxidative stress modulates angiotensin (Ang) II type 1 receptor (AT(1)R) expression and function. Ang II activates renal Na(+)/H(+) exchanger 3 (NHE3) to increase sodium reabsorption, but the mechanisms are still elusive. In addition, the upregulation of AT(1)R during oxidative stress could promote sodium retention and lead to an increase in blood pressure.

Oxidative stress alters renal D1 and AT1 receptor functions and increases blood pressure in old rats.

Aging is associated with an increase in oxidative stress and blood pressure (BP). Renal dopamine D1 (D1R) and angiotensin II AT1 (AT1R) receptors maintain sodium homeostasis and BP. We hypothesized that age-associated increase in oxidative stress causes altered D1R and AT1R functions and high BP in aging.

Exercise reduces oxidative stress but does not alleviate hyperinsulinemia or renal dopamine D1 receptor dysfunction in obese rats.

Impairment of renal dopamine D1 receptor (D1R)-mediated natriuresis is associated with hypertension in humans and animal models, including obese Zucker rats. We have previously reported that treatment of these rats with antioxidants or insulin sensitizers reduced insulin levels and oxidative stress, restored D1R-mediated natriuresis, and reduced blood pressure. Furthermore, the redox-sensitive transcription factor, nuclear factor-κB (NF-κB), has been implicated in impairment of D1R-mediated natriuresis during oxidative stress.

Inflammation compromises renal dopamine D1 receptor function in rats.

We tested the effects of inflammation on renal dopamine D1 receptor signaling cascade, a key pathway that maintains sodium homeostasis and blood pressure during increased salt intake. Inflammation was produced by administering lipopolysaccharide (LPS; 4 mg/kg ip) to rats provided without (normal salt) and with 1% NaCl in drinking water for 2 wk (high salt). Control rats had saline injection and received tap water.

Exercise activates redox-sensitive transcription factors and restores renal D1 receptor function in old rats.

We have previously reported that age-associated oxidative stress via protein kinase C (PKC) increases D1 receptor (D1R) phosphorylation and causes D1R-G protein uncoupling in renal proximal tubules (RPTs) of old Fischer 344 rats. This results in reduced ability of D1R agonist SKF-38393 to inhibit Na+-K+-ATPase in RPTs of old rats. Here, we studied the effect of treadmill exercise on markers of oxidative stress, PKC, D1R phosphorylation, D1R-G protein coupling, and Na+-K+-ATPase activity in RPTs of adult and old rats.

Inhibition of natriuretic factors increases blood pressure in rats.

Renal dopamine and nitric oxide contribute to natriuresis during high-salt intake which maintains sodium and blood pressure homeostasis. We wanted to determine whether concurrent inhibition of these natriuretic factors increases blood pressure during high-sodium intake. Male Sprague-Dawley rats were divided into the following groups: 1) vehicle (V)-tap water, 2) NaCl-1% NaCl drinking water, 3) 30 mM l-buthionine sulfoximine (BSO), an oxidant, 4) BSO plus NaCl, and 5) BSO plus NaCl with 1 mM tempol (antioxidant).