Abstract
Key points Body Na+ content is tightly controlled by regulated urinary Na+ excretion.The intrarenal mechanisms mediating adaptation to variations in dietary Na+ intake are incompletely characterized.We confirmed and expanded observations in mice that variations in dietary Na+ intake do not alter the glomerular filtration rate but alter the total and cell‐surface expression of major Na+ transporters all along the kidney tubule.Low dietary Na+ intake increased Na+ reabsorption in the proximal tubule and decreased it in more distal kidney tubule segments.High dietary Na+ intake decreased Na+ reabsorption in the proximal tubule and increased it in distal segments with lower energetic efficiency.The abundance of apical transporters and Na+ delivery are the main determinants of Na+ reabsorption along the kidney tubule.Tubular O2 consumption and the efficiency of sodium reabsorption are dependent on sodium diet. Na+ excretion by the kidney varies according to dietary Na+ intake. We undertook a systematic study of the effects of dietary salt intake on glomerular filtration rate (GFR) and tubular Na+ reabsorption. We examined the renal adaptive response in mice subjected to 7 days of a low sodium diet (LSD) containing 0.01% Na+, a normal sodium diet (NSD) containing 0.18% Na+ and a moderately high sodium diet (HSD) containing 1.25% Na+. As expected, LSD did not alter measured GFR and increased the abundance of total and cell‐surface NHE3, NKCC2, NCC, α‐ENaC and cleaved γ‐ENaC compared to NSD. Mathematical modelling predicted that tubular Na+ reabsorption increased in the proximal tubule but decreased in the distal nephron because of diminished Na+ delivery. This prediction was confirmed by the natriuretic response to diuretics targeting the thick ascending limb, the distal convoluted tubule or the collecting system. On the other hand, HSD did not alter measured GFR but decreased the abundance of the aforementioned transporters compared to NSD. Mathematical modelling predicted that tubular Na+ reabsorption decreased in the proximal tubule but increased in distal segments with lower transport efficiency with respect to O2 consumption. This prediction was confirmed by the natriuretic response to diuretics. The activity of the metabolic sensor adenosine monophosphate‐activated protein kinase (AMPK) was related to the changes in tubular Na+ reabsorption. Our data show that fractional Na+ reabsorption is distributed differently according to dietary Na+ intake and induces changes in tubular O2 consumption and sodium transport efficiency.
Highlights
Average daily Na+ intake in modern societies is largely higher than 2 g (87 mmol/24 h), the value recommended for adults by the World Health Organization 2012 guidelines
We examined the renal adaptive response in mice subjected to 7 days of a low sodium diet (LSD) containing 0.01% Na+, a normal sodium diet (NSD) containing 0.18% Na+ and a moderately high sodium diet (HSD) containing 1.25% Na+
Salt may play an essential role in the progression of chronic kidney disease (CKD), which is characterized by decreased glomerular filtration rate, albuminuria as well as glomerular and tubular-interstitial fibrosis, both in a blood pressure (BP)-dependent and in a BP-independent manner (Boero et al 2002; Kotchen et al 2013)
Summary
Average daily Na+ intake in modern societies is largely higher than 2 g (87 mmol/24 h), the value recommended for adults by the World Health Organization 2012 guidelines (http://www.who.int/nutrition/publications/ guidelines/sodium_intake/en/). A high salt intake is associated with adverse health outcomes in relation to increased blood pressure (BP) (Meneton et al 2005). Salt may play an essential role in the progression of chronic kidney disease (CKD), which is characterized by decreased glomerular filtration rate, albuminuria as well as glomerular and tubular-interstitial fibrosis, both in a BP-dependent and in a BP-independent manner (Boero et al 2002; Kotchen et al 2013). Dietary salt restriction has been shown to reduce BP, albuminuria and kidney fibrosis (Lambers Heerspink et al 2012). Recent studies suggested that both very low and high Na+ intakes are associated with increased mortality, consistent with a U- or J-shaped association between urinary Na+ excretion and cardiovascular outcomes (Graudal et al 2014; O’Donnell et al 2014; Pfister et al 2014). While not universally accepted (Cogswell et al 2016), this non-linear relationship between Na+ intake and cardiovascular outcomes may indicate that the human cardio-renal system is best adapted to an optimal range of Na+ intake
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