Prediction of development and maintenance of high albuminuria during chronic renin–angiotensin suppression by plasma proteomics

Baldán-Martín, Montserrat; Cuesta, Fernando de la; Alvarez-Llamas, Gloria; González-Calero, Laura; Ruiz‐Hurtado, Gema; Moreno‐Luna, Rafael; Mouriño-Álvarez, Laura; Sastre-Oliva, Tamara; Segura, Julián; Padial, Luis Rodrı́guez; Vivanco, Fernando; Ruilope, Luís M.; Barderas, María G.

doi:10.1016/j.ijcard.2015.05.148

Cited by 19 publications

(10 citation statements)

References 27 publications

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“…Albuminuria is an indicator of cardiovascular risk and of end-stage renal disease. We recently reported significant alterations in proteins from urine and plasma in response to albuminuria and its de novo development in these hypertensive patients [ 14 , 16 , 17 ], demonstrating that subjacent biological mechanisms have a measurable molecular phenotype in biological fluids which, in some cases, may allow for anticipating the response of the traditional clinical marker (albuminuria). Exosomes have been shown to reflect molecular changes taking place in kidney tissue from patients with diabetic nephropathy [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Urinary exosomes reveal protein signatures in hypertensive patients with albuminuria

et al. 2017

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Albuminuria is an indicator of cardiovascular risk and renal damage in hypertensive individuals. Chronic renin–angiotensin system (RAS) suppression facilitates blood pressure control and prevents development of new-onset-albuminuria. A significant number of patients, however, develop albuminuria despite chronic RAS blockade, and the physiopathological mechanisms are underexplored. Urinary exosomes reflect pathological changes taking place in the kidney. The objective of this work was to examine exosomal protein alterations in hypertensive patients with albuminuria in the presence of chronic RAS suppression, to find novel clues underlying its development. Patients were followed-up for three years and were classified as: a) patients with persistent normoalbuminuria; b) patients developing de novo albuminuria; and c) patients with maintained albuminuria. Exosomal protein alterations between groups were identified by isobaric tag quantitation (iTRAQ). Confirmation was approached by target analysis (SRM). In total, 487 proteins were identified with high confidence. Specifically, 48 proteins showed an altered pattern in response to hypertension and/or albuminuria. Out of them, 21 proteins interact together in three main functional clusters: glycosaminoglycan degradation, coagulation and complement system, and oxidative stress. The identified proteins constitute potential targets for drug development and may help to define therapeutic strategies to evade albuminuria progression in hypertensive patients chronically treated.

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Section: Discussionmentioning

confidence: 99%

Urinary exosomes reveal protein signatures in hypertensive patients with albuminuria

et al. 2017

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“…Thus, this is a clinical question of extreme importance, and there are no current studies on it apart from previous research from our group. [14][15][16] The proteomic analysis has allowed identifying 2 proteomic signatures involved in the development of de novo and sustained albuminuria, which are related to inflammation, immune response, and endoplasmic reticulum stress. The relevance of our findings is that this strategy may contribute to adequate risk assessment and earlier intervention and better outcome of these patients.…”

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confidence: 99%

“…15,16 Recently, substantial improvements in the entire mass spectrometry-based proteomics pipeline, including sample preparation, liquid chromatography-mass spectrometry hardware, and data analysis, have been produced. In this study, we present the application of an omics strategy to approach the unbiased, nontargeted, study of albuminuria in hypertensive patients with RAS blockade searching for predictors and chronic organ damage markers in blood plasma ( Figure 1A).…”

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Plasma Molecular Signatures in Hypertensive Patients With Renin–Angiotensin System Suppression

et al. 2016

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A lbuminuria is a risk factor strongly associated with cardiovascular and renal complications particularly when diabetes mellitus and hypertension are present. However, in the absence of these 2 processes, albuminuria can be equally relevant as a predictor.1 These facts reflect the enormous relevance of albuminuria to monitor cardiovascular disease, the first cause of death in the general population.2 Different factors promote the development of albuminuria 3 and lead finally to an increased albumin leakage through the glomerular barrier. [4][5][6][7] Renin-angiotensin system (RAS) suppression is considered the therapy of choice to prevent the development of new-onset albuminuria in naïf patients 8,9 and to diminish the amount of excreted albuminuria. 10 The positive effect depends on a reduction in blood pressure, 11 as well as a modification of intraglomerular hemodynamics and permeability.12 Recent studies conducted by our group have shown that despite an apparently adequate RAS suppression, a relevant percentage of hypertensive patients develop de novo albuminuria pointing to a progression of cardiovascular disease probably facilitated by an inappropriate therapeutic response to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. 13Moreover, we have also found an increased systemic oxidative damage in hypertensive patients who develop albuminuria under chronic RAS suppression suggesting that oxidative stress is one of the mechanisms underlying the development of albuminuria 14 in this situation. These considerations highlight the need to continue searching for potential mechanisms and indicators of the development and progression of albuminuria in hypertensive patients under RAS suppression, considering that it will contribute Abstract-Albuminuria is a risk factor strongly associated with cardiovascular disease, the first cause of death in the general population. It is well established that renin-angiotensin system suppressors prevent the development of new-onset albuminuria in naïf hypertensive patients and diminish its excretion, but we cannot forget the percentage of hypertensive patients who develop de novo albuminuria. Here, we applied multiple proteomic strategy with the purpose to elucidate specific molecular pathways involved in the pathogenesis and provide predictors and chronic organ damage indicators. Briefly, 1143 patients were followed up for a minimum period of 3 years. One hundred and twenty-nine hypertensive patients chronically renin-angiotensin system suppressed were recruited, classified in 3 different groups depending on their albuminuria levels (normoalbuminuria, de novo albuminuria, and sustained albuminuria), and investigated by multiple proteomic strategies. Our strategy allowed us to perform one of the deepest plasma proteomic analysis to date, which has shown 2 proteomic signatures: (1) with predictive value of de novo albuminuria and (2) sustained albuminuria indicator proteins. These proteins are involved in inflammation, immune as well as in the proteasome...

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“…These patients show a characteristic inflammatory signature in both plasma [2, 3] and urine [4]. In this context, increased shear stress, endothelial dysfunction [5] and oxidative stress [6] in the whole circulatory system arises and therefore additional therapies need to be addressed to prevent future events and avoid organ damage.…”

Section: Introductionmentioning

confidence: 99%

Kalirin and CHD7: novel endothelial dysfunction indicators in circulating extracellular vesicles from hypertensive patients with albuminuria

Cuesta¹,

Baldán-Martín

Moreno‐Luna

et al. 2017

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Despite of the great advances in anti-hypertensive therapies, many patients under Renin-Angiotensin- System (RAS) suppression develop albuminuria, which is a clear indicator of therapeutic inefficiency. Hence, indicators of vascular function are needed to assess patients’ condition and help deciding future therapies.Proteomic analysis of circulating extracellular vesicles (EVs) showed two proteins, kalirin and chromodomain-helicase-DNA-binding protein 7 (CHD7), increased in albuminuric patients. A positive correlation of both with the expression of the endothelial activation marker E-selectin was found in EVs. In vitro analysis using TNFα-treated adult human endothelial cells proved their involvement in endothelial cell activation.Hence, we propose protein levels of kalirin and CHD7 in circulating EVs as novel endothelial dysfunction markers to monitor vascular condition in hypertensive patients with albuminuria.

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Prediction of development and maintenance of high albuminuria during chronic renin–angiotensin suppression by plasma proteomics

Cited by 19 publications

References 27 publications

Urinary exosomes reveal protein signatures in hypertensive patients with albuminuria

Urinary exosomes reveal protein signatures in hypertensive patients with albuminuria

Plasma Molecular Signatures in Hypertensive Patients With Renin–Angiotensin System Suppression

Kalirin and CHD7: novel endothelial dysfunction indicators in circulating extracellular vesicles from hypertensive patients with albuminuria

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