Fructose Stimulates Na/H Exchange Activity and Sensitizes the Proximal Tubule to Angiotensin II

Abstract

Abstract-The proximal nephron reabsorbs 60% to 70% of the fluid and sodium and most of the filtered bicarbonate via Na/H exchanger 3. Enhanced proximal nephron transport is implicated in hypertension. Our findings show that a fructose-enriched diet causes salt sensitivity. We hypothesized that fructose stimulates luminal Na/H exchange activity and sensitizes the proximal tubule to angiotensin II. Na/H exchange was measured in rat proximal tubules as the rate of intracellular pH (pH i ) recovery in fluorescent units/s. Replacing 5 mmol/L glucose with 5 mmol/L fructose increased the rate of pH i recovery (1.8±0.6 fluorescent units/s; P<0.02; n=8). Staurosporine, a protein kinase C inhibitor, blocked this effect. We studied whether this effect was because of the addition of fructose or removal of glucose. The basal rate of pH i recovery was first tested in the presence of a 0.6-mmol/L glucose and 1, 3, or 5 mmol/L fructose added in a second period. The rate of pH i recovery did not change with 1 mmol/L but it increased with 3 and 5 mmol/L of fructose. Adding 5 mmol/L glucose caused no change. Removal of luminal sodium blocked pH i recovery. With 5.5 mmol/L glucose, angiotensin II (1 pmol/L) did not affect the rate of pH i recovery (change, -1.1±0.5 fluorescent units/s; n=9) but it increased the rate of pH i recovery with 0.6 mmol/L glucose/5 mmol/L fructose (change, 4.0±2.2 fluorescent units/s; P<0.02; n=6). We conclude that fructose stimulates Na/H exchange activity and sensitizes the proximal tubule to angiotensin II. This mechanism is likely dependent on protein kinase C. These results may partially explain the mechanism by which a fructose diet induces

Metabolic and Kidney Diseases in the Setting of Climate Change, Water Shortage, and Survival Factors

“…44,45 We recently showed that orally administered fructose augments circulating vasopressin levels (as determined by measuring copeptin, a validated biomarker for vasopressin 46 ) and urinary concentration in dehydrated rats. 47 Fructose also stimulates urinary sodium reabsorption 48 and reduces urea excretion 49 similar to vasopressin.…”

Activation of Renal (Pro)Renin Receptor Contributes to High Fructose-Induced Salt Sensitivity

“…Excessive fructose intake has been linked to the epidemics of diabetes mellitus 1 , obesity 2 , renal failure 3, 4 , and hypertension 2 . Many previous studies have reported that feeding rats with a high-fructose (HF) diet causes hypertension 2 , whereas Brands et al 3 and Bezerra et al 4 showed that an HF diet alone did not increase blood pressure (BP) in rats, but induced salt-sensitive hypertension in conjunction with a high-salt (HS) diet as assessed by using radiotelemetry 5–7 . D'Angelo et al also pointed out that previous reports of HF-induced hypertension reflect a heightened response to restraint and thermal stress, leading to an increase in sympathetic output and contributing to the increase in BP, as monitored by using the tail-cuff method 8 .…”

Renal sodium handling and sodium sensitivity

“…Stationary micro-infusion of fructose into the proximal tubules of Wistar rats caused a dose-dependent increase in NHE3 activity, and it was demonstrated both in vivo and in vitro that fructose causes phosphorylation and activation of NHE3 via downregulation of a PKA signaling pathway [62]. In separate studies dietary fructose supplementation prior to and during increased dietary salt intake evokes the development of salt-sensitive hypertension in the salt resistant Sprague-Dawley rat [63]. Companion ex vivo studies of isolated and perfused proximal tubules suggest that 1) fructose stimulates NHE3 activity in a PKC-dependent manner and, 2) that Ang-II mediated-stimulation of NHE3 activity is enhanced by fructose [63].…”

“…In separate studies dietary fructose supplementation prior to and during increased dietary salt intake evokes the development of salt-sensitive hypertension in the salt resistant Sprague-Dawley rat [63]. Companion ex vivo studies of isolated and perfused proximal tubules suggest that 1) fructose stimulates NHE3 activity in a PKC-dependent manner and, 2) that Ang-II mediated-stimulation of NHE3 activity is enhanced by fructose [63]. Together, these studies suggest that a typical Western diet, which features low potassium intake and high fructose and sodium intake, promotes the prevalence salt-sensitive hypertension by modulating renal sodium transporter activity and expression to drive renal sodium retention (Table 3).…”