Renal Effects and Underlying Molecular Mechanisms of Long-Term Salt Content Diets in Spontaneously Hypertensive Rats.

Rebeca Caldeira Machado Berger,Renato De Oliveira Crajoinas,Daisy Motta-Santos,Robson Augusto Souza Santos,Isabella Binotti Araújo,Adriana Castello Costa Girardi,Ludimila Forechi,Paula Frizera Vassallo,Breno Valentim Nogueira,Flávia Letícia Martins,Marilene Luzia Oliveira,José Geraldo Mill,Utpal Sen

doi:10.1371/journal.pone.0141288

Rebeca Caldeira Machado Berger, Renato De Oliveira Crajoinas + Show 11 more

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https://doi.org/10.1371/journal.pone.0141288

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Abstract

Several evidences have shown that salt excess is an important determinant of cardiovascular and renal derangement in hypertension. The present study aimed to investigate the renal effects of chronic high or low salt intake in the context of hypertension and to elucidate the molecular mechanisms underlying such effects. To this end, newly weaned male SHR were fed with diets only differing in NaCl content: normal salt (NS: 0.3%), low salt (LS: 0.03%), and high salt diet (HS: 3%) until 7 months of age. Analysis of renal function, morphology, and evaluation of the expression of the main molecular components involved in the renal handling of albumin, including podocyte slit-diaphragm proteins and proximal tubule endocytic receptors were performed. The relationship between diets and the balance of the renal angiotensin-converting enzyme (ACE) and ACE2 enzymes was also examined. HS produced glomerular hypertrophy and decreased ACE2 and nephrin expressions, loss of morphological integrity of the podocyte processes, and increased proteinuria, characterized by loss of albumin and high molecular weight proteins. Conversely, severe hypertension was attenuated and renal dysfunction was prevented by LS since proteinuria was much lower than in the NS SHRs. This was associated with a decrease in kidney ACE/ACE2 protein and activity ratio and increased cubilin renal expression. Taken together, these results suggest that LS attenuates hypertension progression in SHRs and preserves renal function. The mechanisms partially explaining these findings include modulation of the intrarenal ACE/ACE2 balance and the increased cubilin expression. Importantly, HS worsens hypertensive kidney injury and decreases the expression nephrin, a key component of the slit diaphragm.

Highlights

The association of the excessive salt intake with hypertension, cardiovascular and renal diseases is well accepted
It is well known that high salt intake strongly contributes to hypertension development and to its complications, including chronic kidney disease [26]
This study showed that a long-term low salt diet (6 months) was able to attenuate the spontaneous hypertension in spontaneously hypertensive rats (SHRs) with a clear renoprotective effect, leading to a reduction in proteinuria doi:10.1371/journal.pone.0141288.g002

Summary

Introduction

The association of the excessive salt intake with hypertension, cardiovascular and renal diseases is well accepted. Salt overload is believed to promote additional non-pressure-related adverse effects, including cardiac hypertrophy, impaired ventricular relaxation, endothelial dysfunction, increased oxidative stress and renal injury. Together, these effects accelerate glomerular damage, interstitial fibrosis and proteinuria [1,2,3,4]. Given the high salt intake found in most of modern populations, the mechanisms by which high levels of salt intake may contribute to cardiovascular and renal injury, and how low salt acts to avoid these effects are of paramount importance. The benefits of low salt diets in cardiovascular disease events have been recently questioned [12,13]

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