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Angiotensin II, reactive oxygen species, and Ca²⁺ signaling in afferent arterioles

Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Submitted 7 April 2005 ; accepted in final form 3 June 2005

In afferent arteriolar vascular smooth muscle cells, ANG II induces a rise in cytosolic Ca²⁺ ([Ca²⁺]_i) via inositol trisphosphate receptor (IP₃R) stimulation and by activation of the adenine diphosphate ribose (ADPR) cyclase to form cyclic ADPR, which sensitizes the ryanodine receptor (RyR) to Ca²⁺. We hypothesize that ANG II stimulation of NAD(P)H oxidases leads to the formation of superoxide anion (O₂^–·), which, in turn, activates ADPR cyclase. Afferent arterioles were isolated from rat kidney with the magnetized microsphere and sieving technique and loaded with fura-2 to measure [Ca²⁺]_i. ANG II rapidly increased [Ca²⁺]_i by 124 ± 12 nM. In the presence of apocynin, a specific inhibitor of NAD(P)H oxidase assembly, the [Ca²⁺]_i response was reduced to 35 ± 5 nM (P < 0.01). Tempol, a superoxide dismutase mimetic, did not alter the [Ca²⁺]_i response to ANG II at a concentration of 10^–4 M (99 ± 12 nM), but 10^–3 M tempol reduced the response to 32 ± 3 nM (P < 0.01). The addition of nicotinamide, an inhibitor of ADPR cyclase, to apocynin or tempol (10^–3 M) resulted in no further inhibition. Measurement of superoxide production with the fluorescent probe tempo 9-AC showed that ANG II caused an increase of 48 ± 20 arbitrary units; apocynin or diphenyl iodonium (an inhibitor of flavoprotein oxidases) inhibited the response by 94%. Hydrogen peroxide (H₂O₂) was studied at physiological (10^–7 M) and higher concentrations. In the presence of H₂O₂ (10^–7 M), neither baseline [Ca²⁺]_i nor the response to ANG II was altered (125 ± 15 nM), whereas H₂O₂ (10^–6 and 10^–5 M) inhibited the [Ca²⁺]_i response to ANG II by 35 and 46%, respectively. We conclude that ANG II rapidly activates NAD(P)H oxidases of afferent arterioles, leading to the formation of O₂^–·, which then stimulates ADPR cyclase to form cADPR. cADPR, by sensitizing the RyR to Ca²⁺, augments the Ca²⁺ response (calcium-induced calcium release) initiated by activation of the IP₃R.

cADP ribose; ryanodine; renal microcirculation; vascular smooth muscle cells; superoxide anion; tempo 9-AC

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