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Comparative Study
. 2012 Sep;60(3):765-9.
doi: 10.1161/HYPERTENSIONAHA.112.199216. Epub 2012 Jul 9.

Angiotensin II type 2 receptor-mediated inhibition of NaCl absorption is blunted in thick ascending limbs from Dahl salt-sensitive rats

Nancy J Hong  1 , Jeffrey L Garvin
Affiliations
Comparative Study

Angiotensin II type 2 receptor-mediated inhibition of NaCl absorption is blunted in thick ascending limbs from Dahl salt-sensitive rats

Nancy J Hong et al. Hypertension. 2012 Sep.

Abstract

NO reduces NaCl absorption by thick ascending limbs (TALs) by inhibiting the Na/K/2Cl cotransporter (NKCC2). We have shown that NO-induced inhibition of Na transport is reduced in Dahl salt-sensitive rat (SS) TALs. Angiotensin II increases NO production in TALs via angiotensin II type 2 receptor (AT(2)R). It is unknown whether AT(2)Rs regulate TAL NaCl absorption and whether this effect is reduced in SS rats. We hypothesized that AT(2)R activation decreases TAL Na transport via NO, and this effect is blunted in SS rats. In the presence of angiotensin II type 1 receptor antagonist losartan, AT(2)R activation with angiotensin II inhibited NKCC2 activity by 32±7% (P<0.03). AT(2)R antagonist PD-123319 abolished the effect of angiotensin II. Activation with the AT(2)R-selective agonist CGP42112A (10 nmol/L) decreased NKCC2 activity by 29±6% (P<0.03). The effect of CGP42112A on NKCC2 activity was blocked by PD-123319 and by NO synthase inhibitor N(G)-nitro-l-arginine methyl ester. In Dahl salt-resistant rat TALs, 1 nmol/L of CGP42112A decreased NKCC2 activity by 23±4% (P<0.01). In SS TALs, it had no effect. TAL AT(2)R mRNA did not differ in SS versus salt-resistant rats. We conclude the following: (1) TAL AT(2)R activation decreases Na absorption; (2) this effect is mediated by AT(2)R-induced stimulation of NO; (3) AT(2)R-induced reduction of NKCC2 activity is blunted in SS rats; and (4) defects in AT(2)R/NO signaling rather than decreased AT(2)R expression likely account for the blunted effect in SS TALs. Impaired AT(2)R-mediated signaling in TALs could contribute to the Na retention associated with salt-sensitive hypertension.

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Figures

Figure 1
Figure 1
A: Angiotensin II (Ang II; 100 nmol/L) in the presence of the AT1R antagonist losartan (Los; 1 µmol/L) inhibits NKCC2 activity in TALs by 32 ±7%. B: In the presence of Los (1 µmol/L) and The AT2R antagonist PD-123319 (PD; 1 µmol/L), the effect of Ang II (100 nmol/L) on NKCC2 activity in TALs is blocked.
Figure 2
Figure 2
A: The AT2R-selective agonist CGP42112A (CGP; 10 nmol/L) inhibits NKCC2 activity in TALs by 29 ± 6%. B: PD (1 µmol/L) blocks the effect of CGP on NKCC2 activity.
Figure 3
Figure 3
The NOS inhibitor L-NAME blocks the effect of CGP (10 nmol/L) on NKCC2 activity in TALs.
Figure 4
Figure 4
CGP (1 nmol/L) inhibits NKCC2 activity in Dahl salt-resistant rat (SR) TALs by 23 ± 4%, but does not decrease NKCC2 activity in Dahl salt-sensitive rat (SS) TALs.
Figure 5
Figure 5
AT2R mRNA does not decrease in TALs from Dahl salt-sensitive rats (SS) compared to TALs from Dahl salt-resistant rats (SR). A: Representative gel of AT2R mRNA and GAPDH mRNA in TALs from SR and SS rats. B: Cumulative data for TAL AT2R mRNA of SS vs. SR normalized to GAPDH mRNA.
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