Abstract 471: Mechanism of Pressure-Natriuresis

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Abstract

Pressure-Natriuresis (P-N) is a major compensatory mechanism that prevents an increase in blood pressure by increasing renal sodium excretion (UNaV). Our group showed that cGMP, at least in part, mediates P-N. cGMP signals from the extracellular space through a yet unidentified receptor in the renal proximal tubule basolateral membrane. We hypothesize that cGMP binds to Na+ K+ ATP-ase (NKA), activating both the Src kinase and the EGFR-Erk-Akt signaling cascades.

In uninephrectomized rats, the renal perfusion pressure (RPP) was increased from 100 to 135 mmHg. During high RPP, UNaV increased 6.3-fold and the ratio of phosphorylated Src (Tyr416)/total Src (pSrc) increased from 0.07±0.02 to 0.71±0.12 μmol/min (P<0.001, N=5 for both). Blocking the NKA ouabain (OUA) binding site by infusing rostafuroxin (RF, a specific OUA antagonist without effect on NKA pump activity) directly into the renal interstitium reduced UNaV 6.4-fold and pSrc to 0.22±0.05 (N=8, P<0.05). Both phosphorylation of Erk 1/2 (p44/42 MAPK) and Akt (Ser473) were increased during the high RPP period (0.35±0.07 to 2.08±0.21; N=6 for both, P<10-4 and 0.39±0.06 to 1.04±0.15; N=8 for both, P<0.01, respectively). However, RF did not decrease pErk and pAkt, likely due to in vivo compensatory processes following NKA blockade.

To delineate the role of cGMP in P-N, we infused cGMP into the renal interstitium. UNaV increased 5.7-fold and pSrc increased from 0.09±0.02 (N=4) to 0.35±0.1 (N=6, P<0.05). OUA infusion was used as a positive control and increased pSrc to 0.77±0.01 (N=4, P<10-6). Coinfusion of cGMP and RF reduced pSrc to 0.15±0.03 (P=0.07, N=6). Surprisingly, RF infusion also decreased pErk from 0.71±0.17 (N=6, in cGMP-infused rats) to 0.33±0.09 (N=6, in cGMP and RF-coinfused rats, P=0.085).

In summary, renal interstitial infusion of an NKA signaling antagonist RF blocks Src activation during both P-N and cGMP-induced natriuresis. P-N-induced Erk and Akt activation is not affected by RF. However, Erk and Akt phosphorylation is reduced during cGMP-induced natriuresis, suggesting a possible competition between cGMP and RF for the same binding site on NKA. The data support the hypothesis that P-N is mediated by extracellular cGMP binding to basolateral NKA, which serves as a receptor.

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