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

Abstract

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...

Urinary exosomes reveal protein signatures in hypertensive patients with albuminuria

“…Urinary exosomes and their potential role in the physiopathological mechanisms responsible for albuminuria development in hypertensive patients under chronic RAS suppression were investigated. Quantitative iTRAQ-LC-MS/MS proteomic analysis was used to explore exosomal protein alterations, allowing deep coverage of the analyzed proteome as previously shown in plasma in this clinical setting [ 14 ]. The present work focused on proteins.…”

“…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 ].…”

Identification of Urinary Biomarkers for Exercise-Induced Immunosuppression by iTRAQ Proteomics

“…It is processed and presented by thymic antigen presenting cells and is likely to participate in shaping the T-cell repertoire [62], which is involved in the regulation of immune function [63,64]. SEMG-1 is upregulated in exosomes secreted by vascular endothelial cells under hypoxic stress conditions [65] and is considered as a new predictor of renal damage [66]. PIP also plays an important role in immune regulation.…”

Utilizing proteomics to understand and define hypertension: where are we and where do we go?

“…Plasma proteomic studies using LC-electrospray-trap MS have identified molecular signatures based on signaling molecules, growth factors, and angiogenesis factors that are predictive of renal disease in patients with hypertension and/or diabetes [76]. A comprehensive proteomic profiling study in 123 hypertensive patients with chronic RAAS suppression has found signatures that predict development of de novo development of albuminuria or indicate stable albuminuria [77]. The signatures were composed of proteins involved in inflammation, immune, and proteasome activation/endoplasmatic reticulum stress.…”