Abstract
Background: The effect of salt on cerebral small vessel disease (SVD) is poorly understood. We assessed the effect of dietary salt on cerebral tissue of the stroke-prone spontaneously hypertensive rat (SHRSP) – a relevant model of sporadic SVD – at both the gene and protein level. Methods: Brains from 21-week-old SHRSP and Wistar-Kyoto rats, half additionally salt-loaded (via a 3-week regime of 1% NaCl in drinking water), were split into two hemispheres and sectioned coronally – one hemisphere for mRNA microarray and qRT-PCR, the other for immunohistochemistry using a panel of antibodies targeting components of the neurovascular unit. Results: We observed differences in gene and protein expression affecting the acute phase pathway and oxidative stress (ALB, AMBP, APOH, AHSG and LOC100129193, up-regulated in salt-loaded WKY versus WKY, >2-fold), active microglia (increased Iba-1 protein expression in salt-loaded SHRSP versus salt-loaded WKY, p<0.05), vascular structure (ACTB and CTNNB, up-regulated in salt-loaded SHRSP versus SHRSP, >3-fold; CLDN-11, VEGF and VGF down-regulated >2-fold in salt-loaded SHRSP versus SHRSP) and myelin integrity (MBP down-regulated in salt loaded WKY rats versus WKY, >2.5-fold). Changes of salt-loading were more pronounced in SHRSP and occurred without an increase in blood pressure in WKY rats. Conclusion: Salt exposure induced changes in gene and protein expression in an experimental model of SVD and its parent rat strain in multiple pathways involving components of the glio-vascular unit. Further studies in pertinent experimental models at different ages would help clarify the short- and long-term effect of dietary salt in SVD.
Highlights
The association between high dietary salt intake and stroke incidence and mortality is well known [1,2]
Salt-loaded versus age-matched non-salt loaded animals – genome wide approach Both strains In the frontal brain section, 59 genes were differentially expressed in salt-loaded Wistar-Kyoto rat (WKY) versus WKY (Figure 1)
We found a small network of genes centred round β-actin (ACTB) which were almost all up-regulated in salt-loaded spontaneously hypertensive stroke-prone rat (SHRSP) versus SHRSP (Figure 3), including some that are functionally related to maintaining the structural integrity of the vascular cytoskeleton (e.g. ACTB, Destrin (DSTN) and β-catenin (CTNNB1))
Summary
The association between high dietary salt intake and stroke incidence and mortality is well known [1,2]. Epidemiology evidence suggests salt intake is associated with increased stroke risk and CVD independent of blood pressure (BP) [3]; the present study, like many others, was conducted in a general (heterogeneous) stroke population and the effect of salt may differ across stroke subtypes. A study of minor ischaemic patients found an association between increased dietary salt intake and greater volume of white matter hyperintensities (WMH), the most frequent feature of small vessel disease (SVD), independent of BP or history of hypertension [4]. We assessed the effect of dietary salt on cerebral tissue of the stroke-prone spontaneously hypertensive rat (SHRSP) – a relevant model of sporadic SVD – at both the gene and protein level.
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