Abstract
BackgroundHigh dietary sodium aggravates renal disease by affecting blood pressure and by its recently shown pro-inflammatory and pro-fibrotic effects. Moreover, pro-inflammatory modification of renal heparan sulfate (HS) can induce tissue remodeling. We aim to investigate if high sodium intake in normotensive rats converts renal HS into a pro-inflammatory phenotype, able to bind more sodium and orchestrate inflammation, fibrosis and lymphangiogenesis.MethodsWistar rats received a normal diet for 4 weeks, or 8% NaCl diet for 2 or 4 weeks. Blood pressure was monitored, and plasma, urine and tissue collected. Tissue sodium was measured by flame spectroscopy. Renal HS and tubulo-interstitial remodeling were studied by biochemical, immunohistochemical and qRT-PCR approaches.ResultsHigh sodium rats showed a transient increase in blood pressure (week 1; p<0.01) and increased sodium excretion (p<0.05) at 2 and 4 weeks compared to controls. Tubulo-interstitial T-cells, myofibroblasts and mRNA levels of VCAM1, TGF-β1 and collagen type III significantly increased after 4 weeks (all p<0.05). There was a trend for increased macrophage infiltration and lymphangiogenesis (both p = 0.07). Despite increased dermal sodium over time (p<0.05), renal concentrations remained stable. Renal HS of high sodium rats showed increased sulfation (p = 0.05), increased L-selectin binding to HS (p<0,05), and a reduction of sulfation-sensitive anti-HS mAbs JM403 (p<0.001) and 10E4 (p<0.01). Hyaluronan expression increased under high salt conditions (p<0.01) without significant changes in the chondroitin sulfate proteoglycan versican. Statistical analyses showed that sodium-induced tissue remodeling responses partly correlated with observed HS changes.ConclusionWe show that high salt intake by healthy normotensive rats convert renal HS into high sulfated pro-inflammatory glycans involved in tissue remodeling events, but not in increased sodium storage.
Highlights
High sodium intake is known to aggrevate renal disease [1,2,3]
We aim to investigate if high sodium intake in normotensive rats converts renal heparan sulfate (HS) into a pro-inflammatory phenotype, able to bind more sodium and orchestrate inflammation, fibrosis and lymphangiogenesis
High sodium rats showed a transient increase in blood pressure and increased sodium excretion (p
Summary
High sodium intake is known to aggrevate renal disease [1,2,3]. We previously showed that high dietary sodium can cause tissue remodeling and a decline in kidney function [4,5,6,7]. Moderate sodium restriction has shown to have a protective effect in chronic kidney disease (CKD) and combining sodium restrictive dietary measures with common treatment regimens for CKD and proteinuria, enhanced the therapeutic effects [4,5,8] The mechanism of this renoprotective effect of sodium restriction has always been ascribed to the decrease in blood pressure [9,10,11]. We hypothesize that high dietary sodium intake convert renal HS into a pro-inflammatory phenotype, able to bind more sodium and orchestrate influx of inflammatory cells, fibrosis and lymphangiogenesis. To this end normotensive healthy male rats were fed with a high sodium diet and compared to sex- and age-matched rats on control diet, followed by evaluation of renal HS proteoglycans, sodium content and renal tissue remodelling. We aim to investigate if high sodium intake in normotensive rats converts renal HS into a pro-inflammatory phenotype, able to bind more sodium and orchestrate inflammation, fibrosis and lymphangiogenesis
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