Abstract 102: Role of Renal Tubular NHE3 for Blood Pressure and Salt Homeostasis

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The Na + /H + exchanger isoform 3 (NHE3) is expressed in the intestine and the kidney where it facilitates Na + absorption and H + secretion. The importance of NHE3 in the kidney for NaCl homeostasis and blood pressure regulation, relative to the intestine, is not known. To investigate this, we examined kidney-specific NHE3 knockout mice (NHE3 loxloxPax8Cre ) and control mice (Con, NHE3 loxlox ) under normal, low or high dietary NaCl intake. Under normal dietary NaCl intake, no significant differences were detected between genotypes in body weight, fluid or food intake, blood pH and plasma Na + , K + or aldosterone levels. However, urinary pH was significantly elevated in NHE3 loxloxPax8Cre mice and GFR was significantly lower (457±20 vs 358±17 μl/min, P<0.05). High NaCl intake (4% for 10 days) had no impact on plasma Na + in Con mice; but plasma Na + concentrations in NHE3 loxloxPax8Cre mice were susceptible to the effects of low NaCl (<0.01% for 10 days) (-3.9±1.0 mM, P<0.05) or high NaCl intake (+2.2±0.6 mM, P<0.05) compared to baseline conditions. Low NaCl diet decreased plasma K + levels in Con mice (-0.5±0.2 mM, P<0.05) but to a significantly greater amount in NHE3 loxloxPax8Cre mice (-1.2±0.1 mM, P<0.05). Plasma aldosterone was not significantly different between Con and NHE3 loxloxPax8Cre mice under low (345±96 vs 498±78 pg/ml) or high NaCl intake (60±19 vs 86±20 pg/ml). Low NaCl intake decreased GFR in Con (-110±13 μl/min, P<0.05) and NHE3 loxloxPax8Cre (-99±8 μl/min, P<0.05) mice, whereas high NaCl intake was without effect on GFR in either genotype. Dietary NaCl did not affect blood pressure in Con mice (low NaCl: 102±3; high NaCl: 102±3 mmHg); however, blood pressure was significantly lower in NHE3 loxloxPax8Cre mice and salt-sensitive (low NaCl: 81±2; high NaCl: 91±2 mmHg, P<0.05). Alterations in the abundances of several Na + transport proteins within the kidney tubule system were also apparent in NHE3 loxloxCre mice under different dietary conditions. In conclusion, renal NHE3 is required to maintain blood pressure and steady state plasma Na + levels when dietary NaCl intake is modified.