title: Fructose stimulates Na/H exchange activity and sensitizes the proximal tubule to angiotensin II.
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 (pHi) recovery in fluorescent units/s. Replacing 5 mmol/L glucose with 5 mmol/L fructose increased the rate of pHi 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 pHi 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 pHi 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 pHi recovery. With 5.5 mmol/L glucose, angiotensin II (1 pmol/L) did not affect the rate of pHi recovery (change, -1.1±0.5 fluorescent units/s; n=9) but it increased the rate of pHi 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 hypertension.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106-4970. pxc273@case.edu.
authors.forename: Pablo D
authors.initials: PD
authors.lastname: Cabral
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Hong
authors.forename: Md Abdul
authors.initials: MA
authors.lastname: Hye Khan
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Ortiz
authors.forename: William H
authors.initials: WH
authors.lastname: Beierwaltes
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Garvin
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D004195:Disease Models, Animal; D005632:Fructose / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017923:Sodium-Hydrogen Exchangers / Q000187:drug effects* / Q000378:metabolism; D013549:Sweetening Agents / Q000494:pharmacology
chemical_list: D017923:Sodium-Hydrogen Exchangers; D013549:Sweetening Agents; D000804:Angiotensin II; D005632:Fructose
keywords: angiotensin II; hypertension; sodium-hydrogen exchanger