Potential spironolactone effects on collagen metabolism biomarkers in patients with uncontrolled blood pressure.

BACKGROUND: An increase in myocardial collagen content may contribute to the development of heart failure; this might be inhibited or reversed by mineralocorticoid receptor antagonists (MRAs). We investigated changes in serum concentrations of the collagen synthesis biomarkers N-terminal propeptide of procollagen type III (PIIINP) (primary outcome) and C-terminal propeptide of procollagen type I (PICP) (secondary outcome) after non-randomised initiation of spironolactone as add-on therapy among patients with resistant hypertension enrolled in the 'Anglo-Scandinavian Cardiac Outcomes' trial (ASCOT). METHODS: An age/sex matching plus propensity-scored logistic regression model incorporating variables related to the outcome and spironolactone treatment was created to compare patients treated with spironolactone for a 9-month period versus matched controls. A within-person analysis comparing changes in serum biomarker concentrations in the 9 months before versus after spironolactone treatment was also performed. RESULTS: Patients included in the between-person analysis (n=146) were well matched: the mean age was 63±7 years and 11% were woman. Serum concentrations of PIIINP and PICP rose in 'controls' and fell during spironolactone treatment (adjusted means +0.52 (-0.05 to 1.09) vs -0.41 (-0.97 to 0.16) ng/mL, p=0.031 for PIIINP and +4.54(-1.77 to 10.9) vs -6.36 (-12.5 to -0.21) ng/mL, p=0.023 for PICP). For the within-person analysis (n=173), spironolactone treatment was also associated with a reduction in PICP (beta estimate=-11.82(-17.53 to -6.10) ng/mL, p<0.001) but not in PIIINP levels. CONCLUSIONS: Treatment with spironolactone was associated with a reduction in serum biomarkers of collagen synthesis independently of blood pressure in patients with hypertension, suggesting that spironolactone might exert favourable effects on myocardial collagen synthesis and fibrosis. Whether this effect might contribute to slowing the progression to heart failure is worth investigating

Restoration of Podocyte Structure and Improvement of Chronic Renal Disease in Transgenic Mice Overexpressing Renin

Proteinuria is a major marker of the decline of renal function and an important risk factor of coronary heart disease. Elevated proteinuria is associated to the disruption of slit-diaphragm and loss of podocyte foot processes, structural alterations that are considered irreversible. The objective of the present study was to investigate whether proteinuria can be reversed and to identify the structural modifications and the gene/protein regulation associated to this reversal.We used a novel transgenic strain of mouse (RenTg) that overexpresses renin at a constant high level. At the age of 12-month, RenTg mice showed established lesions typical of chronic renal disease such as peri-vascular and periglomerular inflammation, glomerular ischemia, glomerulosclerosis, mesangial expansion and tubular dilation. Ultrastructural analysis indicated abnormal heterogeneity of basement membrane thickness and disappearance of podocyte foot processes. These structural alterations were accompanied by decreased expressions of proteins specific of podocyte (nephrin, podocin), or tubular epithelial cell (E-cadherin and megalin) integrity. In addition, since TGFbeta is considered the major pro-fibrotic agent in renal disease and since exogenous administration of BMP7 is reported to antagonize the TGFbeta-induced phenotype changes in kidney, we have screened the expressions of several genes belonging in the TGFbeta/BMP superfamily. We found that the endogenous inhibitors of BMPs such as noggin and Usag-1 were several-fold activated inhibiting the action of BMPs and thus reinforcing the deleterious action of TGFbeta.Treatment with an AT1 receptor antagonist, at dose that did not decrease arterial pressure, gradually reduced albuminuria. This decrease was accompanied by re-expression of podocin, nephrin, E-cadherin and megalin, and reappearance of podocyte foot processes. In addition, expressions of noggin and Usag-1 were markedly decreased, permitting thus activation of the beneficial action of BMPs.These findings show that proteinuria and alterations in the expression of proteins involved in the integrity and function of glomerular and renal epithelial phenotype are reversible events when the local action of angiotensin II is blocked, and provide hope that chronic renal disease can be efficiently treated

Régression et progression de l'insuffisance rénale chronique chez une nouvelle souche de souris hypertendues (rôles et régulations de la balance endogène du TGFb/BMP-7)

Pour comprendre les mécanismes mis en jeu dans l évolution de l insuffisance rénale chronique (IRC) une nouvelle souche de souris transgénique est utilisée. Elle présente une hypertension associée à une IRC progressive. Les phases de progression de l IRC et la régulation de la voie du TGFb/BMPs sont étudiées dans le rein et le cœur afin de mettre en évidence un parallélisme de régulation. Puis un traitement bloquant l action de l angiotensine II est donné sans faire diminuer la pression artérielle systémique. A 12 mois, les lésions tubulaires et glomérulaires sont importantes. Le traitement permet une récupération de la fonction rénale et une régression partielle des lésions. Cette amélioration est accompagnée par des variations de l expression des membres de la famille TGFb/BMPs. Ces données montrent que la protéinurie et les modifications d expression des protéines impliquées dans l intégrité et la fonction rénale sont réversibles quand l action locale de l ang II est bloquée. Ces changements sont associés à des altérations de l expression de la famille des TGFb/BMPs ouvrant de nouvelles voies thérapeutiques, à la fois au niveau rénal et cardiaque.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

[Role of cell plasticity in progression and regression of renal fibrosis]

National audienceWith the increasing incidence of chronic renal diseases worldwide, there is an urgent need to understand the mechanisms involved in progression of renalfibrosis. Independently of the underlying cause or trigger, progression of renalfibrosis is mainly characterized by excessive synthesis and abnormal accumulation of extracellular matrix proteins in renal mesenchymal cells. These cells are mainly myofibroblasts deriving from phenotypic transformation of a variety of renal cells, including vascular smooth muscle cells, mesangial cells, tubular epithelial cells, endothelial cells, and pericytes. Recent animal studies showing the regression of renal fibrosis during curative therapy suggest that this phenotypic "transition" is reversible. The plasticity of podocytes controlling glomerular filtration may also play a role in the progression/regression of fibrosis in this settin

Non-immunization associated with increased risk of sudden unexpected death in infancy: A national case–control study

International audienceObjective: In the context of vaccine scepticism, our study aimed to analyse the association between immunization status and the occurrence of sudden unexpected death in infancy (SUDI). Study design: A multi-centre case–control study was conducted between May 2015 and June 2017 with data from the French national SUDI registry (OMIN) for 35 French regional SUDI centres. Cases were infants under age 1 year who died from SUDI and who were registered in OMIN. Controls, matched to cases by age and sex at a 2:1 ratio, were infants admitted to Nantes University Hospital. All immunization data for diphtheria (D), tetanus (T), acellular pertussis (aP), inactivated poliovirus (IPV), Haemophilus influenzae b (Hib), hepatitis B (HB) and 13-valent pneumococcal conjugate vaccine (PCV13) were collected by a physician. Cases and controls were considered immunized if at least one dose of vaccine was administered. Results: A total of 91 cases and 182 controls were included. The median age was 131 days (interquartile range 98–200.0) and the sex ratio (M/F) was about 1.1. For all vaccines combined (D-T-aP-IPV-Hib and PCV13), 22 % of SUDI cases versus 12 % of controls were non-immunized, which was significantly associated with SUDI after adjustment for potential adjustment factors (adjusted odds ratio 2.01 [95 % confidence interval 1.01–3.98, p = 0,047]). Conclusions: Non-immunization for D-T-aP-IPV-Hib-HB and PCV13 was associated with increased risk of SUDI. This result can be used to inform the general public and health professionals about this risk of SUDI in case of vaccine hesitancy

Improvement of renal histology following AT1 receptor antagonism.

<p>Representative example of renal cortical histology revealed by Mason's trichrome in 12 month old wild type (A) and RenTg mice before (B) and after (C) 6 weeks of irbesartan administration. Note the substantial improvement of the renal histology following therapy with the AT1 receptor antagonist. Bar = 200 µm.</p

Reestablishment of normal podocyte phenotype after AT1 receptor antagonism.

<p>Quantitative RT-PCR analysis of the expression of genes involved in the podocyte structure such as podocin (A) and nephrin (B) in the renal cortex of wild type and RenTg mice before and after irbesartan treatment, and representative examples of podocin expression in glomeruli of wild type (C) and RenTg mice before (D) and after (E) irbesartan treatment. The expressions of podocin and nephrin in the RenTg mice returned to control values following irbesartan administration. Bar = 50 µm. Values are mean±SEM; n = 5, 9 and 13 for wild type and RenTg mice before and after irbesartan, respectively; ** P<0,01 vs WT; ^## P<0,001 vs RenTg.</p

Therapy with AT1 receptor antagonist led to reappearance of proteins characterizing normal function of proximal tubules.

<p>Representative examples of the expression of proteins typical of the structure and function of proximal tubules such as E-cadherin and megalin. E-cadherin immunostaining in wild type (A) and RenTg mice before (B) and after (C) irbesartan treatment. Quantification by morphometric analysis is presented in D. Megalin expression in wild type (E) and RenTg mice before (F) and after (G) irbesartan treatment. Quantification by morphometric analysis is presented in H. Note that the blunted expression of both proteins in RenTg mice was increased to normal levels following treatment with the AT1 receptor antagonist. Bar = 200 µm. Values are mean±SEM; n = 5, 9 and 13 for wild type and RenTg mice before and after irbesartan, respectively; ** P<0,01 vs WT; ^# P<0,05 or ^## P<0,001 vs RenTg.</p

List of the primers used for the Real Time-PCR of the different genes as mentioned in the results section.

<p>List of the primers used for the Real Time-PCR of the different genes as mentioned in the results section.</p