Nox1-derived oxidative stress as a common pathogenic link between obesity and hyperoxaluria-related kidney injury

Medina, J. Sáenz; Muñoz, Mercedes; Sánchez, Ana; Rodríguez, Claudia; Jorge, Eduardo; Corbacho, C.; Izquierdo, Daylin Mirabal; Santos, Martín; Donoso, E; Virumbrales, E.; Ramil, Elvira; Coronado, María José; Prieto, Dolores; Carballido, Joaquı́n

doi:10.1007/s00240-019-01170-w

Cited by 7 publications

(17 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, patients with microalbuminuria showed higher NOX1, but lower NOX2, levels compared to normotensive individuals (S1 Fig). The higher NOX1 levels in those patients is in agreement with previous preclinical data showing that NOX1 is not associated with elevation of blood pressure but with renal oxidative stress in a model of chronic hypertension [6] and renal pathology [31][32][33].…”

Section: Nox5 Protein Levels Are Increased In Hypertensive Patientssupporting

confidence: 91%

NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype

et al. 2020

View full text Add to dashboard Cite

Hypertension is the most important cause of death and disability in the elderly. In 9 out of 10 cases, the molecular cause, however, is unknown. One mechanistic hypothesis involves impaired endothelium-dependent vasodilation through reactive oxygen species (ROS) formation. Indeed, ROS forming NADPH oxidase (Nox) genes associate with hypertension, yet target validation has been negative. We re-investigate this association by molecular network analysis and identify NOX5, not present in rodents, as a sole neighbor to human vasodilatory endothelial nitric oxide (NO) signaling. In hypertensive patients, endothelial microparticles indeed contained higher levels of NOX5—but not NOX1, NOX2, or NOX4—with a bimodal distribution correlating with disease severity. Mechanistically, mice expressing human Nox5 in endothelial cells developed—upon aging—severe systolic hypertension and impaired endothelium-dependent vasodilation due to uncoupled NO synthase (NOS). We conclude that NOX5-induced uncoupling of endothelial NOS is a causal mechanism and theragnostic target of an age-related hypertension endotype. Nox5 knock-in (KI) mice represent the first mechanism-based animal model of hypertension.

show abstract

Section: Nox5 Protein Levels Are Increased In Hypertensive Patientssupporting

confidence: 91%

NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In animal models of hyperoxaluria and CaOx deposition, the oxidative stress-mediated inflammatory response by the renal cells to the deposition of CaOx crystals has also been proven [47]. Furthermore, in a recent study performed by our group, oxidative stress associated with Nox1 upregulation along with Nox4 down regulation and an inflammatory response mediated by an elevation of TNFα, COX-2, NF-κB, MCP-1, and OPN have been demonstrated in the kidney of hyperoxaluric rats [48]. Other studies have demonstrated that inhibiting the renin-angiotensin system [49] or decreasing Nox1 and p22 phox subunit expression through the administration of atorvastatin inhibits NADPH oxidase-derived OS, inflammation and crystal deposition in rats with experimentally induced hyperoxaluria [50].…”

Section: Pathogenesis Of Urolithiasismentioning

confidence: 82%

Endothelial Dysfunction: An Intermediate Clinical Feature between Urolithiasis and Cardiovascular Diseases

Medina

Muñoz

Rodríguez

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

An epidemiological relationship between urolithiasis and cardiovascular diseases has extensively been reported. Endothelial dysfunction is an early pathogenic event in cardiovascular diseases and has been associated with oxidative stress and low chronic inflammation in hypertension, coronary heart disease, stroke or the vascular complications of diabetes and obesity. The aim of this study is to summarize the current knowledge about the pathogenic mechanisms of urolithiasis in relation to the development of endothelial dysfunction and cardiovascular morbidities. Methods: A non-systematic review has been performed mixing the terms “urolithiasis”, “kidney stone” or “nephrolithiasis” with “cardiovascular disease”, “myocardial infarction”, “stroke”, or “endothelial dysfunction”. Results: Patients with nephrolithiasis develop a higher incidence of cardiovascular disease with a relative risk estimated between 1.20 and 1.24 and also develop a higher vascular disease risk scores. Analyses of subgroups have rendered inconclusive results regarding gender or age. Endothelial dysfunction has also been strongly associated with urolithiasis in clinical studies, although no systemic serum markers of endothelial dysfunction, inflammation or oxidative stress could be clearly related. Analysis of urine composition of lithiasic patients also detected a higher expression of proteins related to cardiovascular disease. Experimental models of hyperoxaluria have also found elevation of serum endothelial dysfunction markers. Conclusions: Endothelial dysfunction has been strongly associated with urolithiasis and based on the experimental evidence, should be considered as an intermediate and changeable feature between urolithiasis and cardiovascular diseases. Oxidative stress, a key pathogenic factor in the development of endothelial dysfunction has been also pointed out as an important factor of lithogenesis. Special attention must be paid to cardiovascular morbidities associated with urolithiasis in order to take advantage of pleiotropic effects of statins, angiotensin receptor blockers and allopurinol.

show abstract

“…It has been reported that renal epithelial injury may be a result of the influence of OS on the kidneys of idiopathic renal stone patients [ 25 ]. Moreover, our group recently reported higher levels of superoxide, mostly derived from NOX-1 in the kidney cortex and renal interlobar artery from an ethylene glycol-induced rat model of urolithiasis [ 26 ]. MDA is one of the most commonly used biomarkers for lipid peroxidation and oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…The implication of macrophage populations in the calcium oxalate crystal formation has been reported in ex vivo models, and the facilitation of crystal formation by M1 macrophages and the protective role of M2 has been described [ 28 ]. On the other hand, our group reported that both MCP-1 and NFkB1 enhanced expression correlated to changes in oxidative stress levels and Nox1 upregulation in an ethylene glycol-induced rat model of urolithiasis [ 26 ]. VCAM-1 is considered as a biomarker and mediator in several cardiovascular disorders, including hypertension, stroke, and coronary heart disease, and is increased in ED [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Urolithiasis Develops Endothelial Dysfunction as a Clinical Feature

Medina

Martínez

Rosado³

et al. 2021

Antioxidants

View full text Add to dashboard Cite

An increased risk of cardiovascular morbidity has been reported in lithiasic patients. In this context, endothelial dysfunction (ED), an earlier status of atherogenesis, has been identified in hyperoxaluria rat models of urolithiasis. Objective: The purpose of this study was to determine the endothelial vascular function in patients with urolithiasis in relation to systemic inflammatory, oxidative stress, and vascular function serum markers. Methods: A cross-sectional study was performed between 27 urolithiasic patients, matched for age and sex, with 27 healthy patients. Endothelial function was assessed by measuring flow-mediated dilation (Celermajer method). Fasting blood was collected to determine metabolic parameters (glucose and lipid profile), along with serum CRP, IL-6, MDA, ADMA, and VCAM-1. Results: Both the control and urolithiasis groups were homogenous in anthropometric, exploration, and general laboratory measures. Flow-mediated dilation (%FMD) was 11.85% (SE: 2.78) lower in the lithiasis group (p < 0.001). No significant differences were achieved between groups when CRP, IL-6, MDA, ADMA, and VCAM-1 were compared, although slightly higher values of CRP, ADMA, and VCAM-1 were detected in the lithiasic group. A correlation was not reached in any of the serum markers when they were related to flow-mediated values, although a slight negative correlation trend was observed in MDA, VCAM-1, and IL-6 values. Conclusions: Endothelial dysfunction constitutes an important disorder related to urolithiasis patients. It must be considered as an early feature responsible for future cardiovascular events. Our study did not find a significant association between inflammatory, oxidative stress, endothelial serum markers, and flow-mediated dilation.

show abstract

Nox1-derived oxidative stress as a common pathogenic link between obesity and hyperoxaluria-related kidney injury

Cited by 7 publications

References 28 publications

NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype

NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype

Endothelial Dysfunction: An Intermediate Clinical Feature between Urolithiasis and Cardiovascular Diseases

Urolithiasis Develops Endothelial Dysfunction as a Clinical Feature

Contact Info

Product

Resources

About