Fructose Acutely Stimulates NHE3 Activity in Kidney Proximal Tubule (original) (raw)
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Nutrients, 2017
Fructose-enriched diets cause salt-sensitive hypertension. Proximal tubules (PTs) reabsorb 70% of the water and salt filtered through the glomerulus. Angiotensin II (Ang II) regulates this process. Normally, dietary salt reduces Ang II allowing the kidney to excrete more salt, thereby preventing hypertension. We hypothesized that fructose-enriched diets enhance the ability of low concentrations of Ang II to stimulate PT transport. We measured the effects of a low concentration of Ang II (10 −12 mol/L) on transport-related oxygen consumption (QO 2), and Na/K-ATPase and Na/H-exchange (NHE) activities and expression in PTs from rats consuming tap water (Control) or 20% fructose (FRUC). In FRUC-treated PTs, Ang II increased QO 2 by 14.9 ± 1.3 nmol/mg/min (p < 0.01) but had no effect in Controls. FRUC elevated NHE3 expression by 19 ± 3% (p < 0.004) but not Na/K-ATPase expression. Ang II stimulated NHE activity in FRUC PT (∆ + 0.7 ± 0.1 Arbitrary Fluorescent units (AFU)/s, p < 0.01) but not in Controls. Na/K-ATPase activity was not affected. The PKC inhibitor Gö6976 blocked the ability of FRUC to augment the actions of Ang II. FRUC did not alter the inhibitory effect of dopamine on NHE activity. We conclude that dietary fructose increases the ability of low concentrations of Ang II to stimulate PT Na reabsorption via effects on NHE.
Nutrients, 2018
Dietary fructose causes salt-sensitive hypertension. Proximal tubules (PTs) reabsorb 70% of the filtered NaCl. Angiotensin II (Ang II), atrial natriuretic peptide (ANP) and norepinephrine (NE) regulate this process. Although Ang II signaling blockade ameliorates fructose-induced salt-sensitive hypertension, basal PT Na+ reabsorption and its sensitivity to the aforementioned factors have not been studied in this model. We hypothesized consuming fructose with a high-salt diet selectively enhances the sensitivity of PT transport to Ang II. We investigated the effects of Ang II, ANP and NE on PT Na reabsorption in rats fed a high-salt diet drinking tap water (HS) or 20% fructose (HS-FRU). Oxygen consumption (QO2) was used as a measure of all ATP-dependent transport processes. Na+/K+-ATPase and Na+/H+-exchange (NHE) activities were studied because they represent primary apical and basolateral transporters in this segment. The effect of 10−12 mol/L Ang II in QO2 by PTs from HS-FRU was lar...
The Role of Salt in the Pathogenesis of Fructose-Induced Hypertension
International Journal of Nephrology, 2011
Metabolic syndrome, as manifested by visceral obesity, hypertension, insulin resistance, and dyslipidemia, is reaching epidemic proportions in the Western World, specifically the United States. Epidemiologic studies suggest that the increased prevalence of metabolic syndrome directly correlates with an increase in the consumption of fructose, mainly in the form of high-fructose corn syrup. This inexpensive alternative to traditional sugar has been increasingly utilized by the food industry as a sweetener since the 1960s. While augmented caloric intake and sedentary lifestyles play important roles in the increasing prevalence of obesity, the pathogenesis of hypertension in metabolic syndrome remains controversial. One intriguing observation points to the role of salt in fructose-induced hypertension. Recent studies in rodents demonstrate that increased dietary fructose intake stimulates salt absorption in the small intestine and kidney tubules, resulting in a state of salt overload, thus setting in motion a cascade of events that will lead to hypertension. These studies point to a novel interaction between the fructose-absorbing transporter, Glut5, and the salt transporters, NHE3 and PAT1, in the intestine and kidney proximal tubule. This paper will focus on synergistic roles of fructose and salt in the pathogenesis of hypertension resulting from salt overload.
Hypertension Associated with Fructose and High Salt: Renal and Sympathetic Mechanisms
Nutrients
Hypertension is a leading cause of cardiovascular and chronic renal disease. Despite multiple important strides that have been made in our understanding of the etiology of hypertension, the mechanisms remain complex due to multiple factors, including the environment, heredity and diet. This review focuses on dietary contributions, providing evidence for the involvement of elevated fructose and salt consumption that parallels the increased incidence of hypertension worldwide. High fructose loads potentiate salt reabsorption by the kidney, leading to elevation in blood pressure. Several transporters, such as NHE3 and PAT1 are modulated in this milieu and play a crucial role in salt-sensitivity. High fructose ingestion also modulates the renin-angiotensin-aldosterone system. Recent attention has been shifted towards the contribution of the sympathetic nervous system, as clinical trials demonstrated significant reductions in blood pressure following renal sympathetic nerve ablation. New...
Cardio-Renal Mechanisms Of Fructose-Induced Salt-Sensitive Hypertension
2021
Dietary consumption of fructose facilitates increased intestinal fluid absorption and renal sodium reabsorption, thereby increasing fluid retention. The net result of this is a sustained increased in extracellular fluid volume that leads to states of hypervolemia and subsequent hypertension. Simultaneously, arterial pressure is being elevated by increased autonomic drive stemming from the sympathetic nervous system and various other endovascular proteins that induce vasoconstriction. Under these conditions, the addition of high dietary sodium promotes hypertension prior to the development of significant metabolic disturbances; the subtlety of which may go unnoticed by patients for prolonged periods. While much is understood regarding the multifactorial pathologies of this model of hypertension, few studies have investigated the chronic effects of this disease and the end-organ damage that may result. The highest consumers of fructose are adolescents and young adults, and despite thi...
Na + -glucose cotransporter 1 (SGLT1)-mediated glucose uptake leads to activation of Na + -H + exchanger 3 (NHE3) in the intestine by a process that is not dependent on glucose metabolism. This coactivation may be important for postprandial nutrient uptake. However, it remains to be determined whether SGLTmediated glucose uptake regulates NHE3-mediated NaHCO 3 reabsorption in the renal proximal tubule. Considering that this nephron segment also expresses SGLT2 and that the kidneys and intestine show significant variations in daily glucose availability, the goal of this study was to determine the effect of SGLTmediated glucose uptake on NHE3 activity in the renal proximal tubule. Stationary in vivo microperfusion experiments showed that luminal perfusion with 5 mM glucose stimulates NHE3-mediated bicarbonate reabsorption. This stimulatory effect was mediated by glycolytic metabolism but not through ATP production. Conversely, luminal perfusion with 40 mM glucose inhibited NHE3 because of cell swelling. Notably, pharmacologic inhibition of SGLT activity by Phlorizin produced a marked inhibition of NHE3, even in the absence of glucose. Furthermore, immunofluorescence experiments showed that NHE3 colocalizes with SGLT2 but not SGLT1 in the rat renal proximal tubule. Collectively, these findings show that glucose exerts a bimodal effect on NHE3. The physiologic metabolism of glucose stimulates NHE3 transport activity, whereas, supraphysiologic glucose concentrations inhibit this exchanger. Additionally, Phlorizin-sensitive SGLT transporters and NHE3 interact functionally in the proximal tubule.
Journal of Biological Chemistry, 1999
Regulation of the renal Na/H exchanger NHE-3 by protein kinase A (PKA) is a key intermediate step in the hormonal regulation of acid-base and salt balance. We studied the role of NHE-3 phosphorylation in this process in NHE-deficient AP-1 cells transfected with NHE-3 and in OKP cells expressing native NHE-3. A dominantnegative PKA-regulatory subunit completely abolished the effect of cAMP on NHE-3 activity demonstrating a role of PKA in the functional regulation of NHE-3 by cAMP. NHE-3 isolated from cAMP-treated cells showed lower phosphorylation by purified PKA in vitro suggesting that NHE-3 is a PKA substrate in vivo. Although changes in NHE-3 whole protein phosphorylation is difficult to detect in response to cAMP addition, the tryptic phosphopeptide map of in vivo phosphorylated NHE-3 showed a complex pattern of constitutive and cAMPinduced phosphopeptides. To test the causal relationship between phosphorylation and activity, we mutated eight serines in the cytoplasmic domain to glycine or alanine. Single or multiple mutants harboring S552A or S605G showed no PKA activation or reduced regulation by PKA activation. Ser-552 and Ser-605 were phosphorylated in vivo. However, multiple mutations of serines other than Ser-552 or Ser-605 also reduced the functional PKA regulation. We conclude that regulation of NHE-3 by PKA in vivo involves complex mechanisms, which include phosphorylation of Ser-552 and Ser-605.
Dietary fructose, salt absorption and hypertension in metabolic syndrome: towards a new paradigm
Acta Physiologica, 2011
The worldwide increase in the incidence of metabolic syndrome correlates with marked increase in total fructose intake in the form of high-fructose corn syrup, beverage and table sugar. Increased dietary fructose intake in rodents has been shown to recapitulate many aspects of metabolic syndrome by causing hypertension, insulin resistance and hyperlipidaemia. Recent studies demonstrated that increased dietary fructose intake stimulates salt absorption in the small intestine and kidney tubules, resulting in a state of salt overload and thus causing hypertension. The absorption of salt (sodium and chloride) in the small intestine is predominantly mediated via the chloride/base exchangers DRA (Down Regulated in Adenoma) (SLC26A3) and PAT1 (Putative Anion Transporter 1) (SLC26A6), and the Na + /H + exchanger NHE3 (Sodium Hydrogen Exchanger3) (SLC9A3). PAT1 and NHE3 also co-localize on the apical membrane of kidney proximal tubule. Luminal fructose stimulated salt absorption in the jejunum and kidney tubules, responses that were significantly diminished in PAT1 null mice. These studies further demonstrated that Glut5 (SLC2A5) is the major fructose-absorbing transporter in the small intestine (and kidney proximal tubule) and plays an essential role in the systemic homeostasis of fructose. Increased dietary fructose intake for several weeks upregulated the expression of NHE3, PAT1 and Glut5 in the intestine and resulted in hypertension in wild-type mice, a response that was almost abolished in PAT1 null mice and abrogated in Glut5 null mice. This article will discuss the interaction of Glut5 with salt-absorbing transporters and review the role of dietary fructose in enhanced salt absorption in intestine and kidney as it relates to the pathogenesis of hypertension in metabolic syndrome.