Angiotensin II-induced contraction is attenuated by nitric oxide in afferent arterioles from the nonclipped kidney in 2K1C

Abstract

, one-clip (2K1C) is a model of renovascular hypertension where we previously found an exaggerated intracellular calcium (Ca i 2ϩ ) response to ANG II in isolated afferent arterioles (AAs) from the clipped kidney (Helle F, Vagnes OB, Iversen BM. Am J Physiol Renal Physiol 291: F140 -F147, 2006). To test whether nitric oxide (NO) ameliorates the exaggerated ANG II response in 2K1C, we studied ANG II (10 Ϫ7 mol/l)-induced calcium signaling and contractility with or without the NO synthase (NOS) inhibitor N G -nitro-L-arginine methyl ester (L-NAME). In AAs from the nonclipped kidney, L-NAME increased the ANG II-induced Ca i 2ϩ response from 0.28 Ϯ 0.05 to 0.55 Ϯ 0.09 (fura 2, 340 nm/380 nm ratio) and increased contraction from 80 Ϯ 6 to 60 Ϯ 6% of baseline (P Ͻ 0.05). In vessels from sham and clipped kidneys, L-NAME had no effect. In diaminofluorescein-FM diacetateloaded AAs from the nonclipped kidney, ANG II increased NOderived fluorescence to 145 Ϯ 34% of baseline (P Ͻ 0.05 vs. sham), but not in vessels from the sham or clipped kidney. Endothelial NOS (eNOS) mRNA and ser-1177 phosphorylation were unchanged in both kidneys from 2K1C, while eNOS protein was reduced in the clipped kidney compared with sham. Cationic amino acid transferase-1 and 2 mRNAs were increased in 2K1C, indicating increased availability of L-arginine for NO synthesis, but counteracted by decreased scavenging of the eNOS inhibitor asymmetric dimethylarginine by dimethylarginine dimethylaminohydrolase 2. In conclusion, the Ca i 2ϩ and contractile responses to ANG II are blunted by NO release in the nonclipped kidney. This may protect the nonclipped kidney from the hypertension and elevated ANG II levels in 2K1C.two-kidney; one-clip; renovascular hypertension TWO-KIDNEY, ONE-CLIP (2K1C) has been studied as an ANG II-dependent model of renovascular hypertension. Earlier studies have demonstrated elevated circulating levels of ANG II, with high ANG II concentration in the cortical tissue of the clipped and nonclipped kidney (20).Renal blood flow (RBF) and intrarenal vascular resistance are controlled by autocrine and paracrine factors as well as myogenic and tubuloglomerular feedback responses. The afferent arteriole (AA) is the main site for RBF and glomerular filtration rate (GFR) regulation and plays an important role during development of 2K1C hypertension (12). The clipped kidney has reduced RBF and GFR (18), impaired autoregulation, and dilated AAs (14). Although RBF autoregulation is reset to higher perfusion pressures, the nonclipped kidney has well-maintained RBF and GFR (6) despite high levels of circulating and cortical tissue ANG II.Previously, we found that the ANG II dose-response curve in AAs from clipped kidneys did not saturate at high doses (10 Ϫ6 M), while those from sham and nonclipped kidneys did (5). The effect of cyclooxygenase (COX) inhibition, together with mRNA and protein (1) expression for the AT 1a receptor, was similar in the nonclipped and clipped kidneys. This indicated that the changed dose-response relationship was...

Angiotensin II Stimulates Thick Ascending Limb NO Production via AT2 Receptors and Akt1-dependent Nitric-oxide Synthase 3 (NOS3) Activation

“…We concluded that Ang II activates PI3K/ Akt1 via the AT 2 receptors, inducing phosphorylation of NOS3 at serines 1177 and 633, resulting in increased production of NO by the TAL. NO has been shown to buffer the actions of Ang II within the renal medulla (5,(45)(46)(47)(48)(49). In the TAL, NO inhibits (15,50), reabsorption whereas O 2 Ϫ stimulates Na ϩ reabsorption (51).…”

Renal neurohormonal regulation in heart failure decompensation

“…Combined inhibition of nitric oxide synthesis and ANG II stimulation uncovers a decreased contractility and almost no nitric oxide production in vessel preparations from animals with heart failure (26). This shows a marked difference from the effect of ANG II on afferent arterioles in high renin hypertension models (22,24) and during ANG II blockade in vivo (61). ANG II increases tubular sodium reabsorption (47), although reabsorption may be decreased by ANG II in the proximal nephron (37,64).…”

AT1 receptor activation regulates the mRNA expression of CAT1, CAT2, arginase-1, and DDAH2 in preglomerular vessels from angiotensin II hypertensive rats

“…ANG II is a key hormone in the regulation of RBF and GFR. However, its effect is in many situations balanced by vasodilators such as vasodilatory prostanoids and nitric oxide (NO) (6). Together these signaling substances are of major importance in the regulation of RBF in the normal kidney and probably more so in hypertensive models where the components of the reninangiotensin system are activated or increased.…”

“…We have recently shown that ANG II-induced NO release controls renal vascular resistance by its ability to adjust the diameter of preglomerular vessels in the nonclipped kidney of two-kidney, one-clip hypertensive (2K1C) animals (6). The nonclipped kidney is subjected to high perfusion pressure and high vascular NO release, while vascular NO production is low in the clipped kidney.…”