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

Abstract

In afferent arteriolar vascular smooth muscle cells, ANG II induces a rise in cytosolic Ca(2+) ([Ca(2+)](i)) via inositol trisphosphate receptor (IP(3)R) stimulation and by activation of the adenine diphosphate ribose (ADPR) cyclase to form cyclic ADPR, which sensitizes the ryanodine receptor (RyR) to Ca(2+). We hypothesize that ANG II stimulation of NAD(P)H oxidases leads to the formation of superoxide anion (O(2)-*, 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 [Ca(2+)](i). ANG II rapidly increased [Ca(2+)](i) by 124 +/- 12 nM. In the presence of apocynin, a specific inhibitor of NAD(P)H oxidase assembly, the [Ca(2+)](i) response was reduced to 35 +/- 5 nM (P < 0.01). Tempol, a superoxide dismutase mimetic, did not alter the [Ca(2+)](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 (H(2)O(2)) was studied at physiological (10(-7) M) and higher concentrations. In the presence of H(2)O(2) (10(-7) M), neither baseline [Ca(2+)](i) nor the response to ANG II was altered (125 +/- 15 nM), whereas H(2)O(2) (10(-6) and 10(-5) M) inhibited the [Ca(2+)](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 O(2)-*, which then stimulates ADPR cyclase to form cADPR. cADPR, by sensitizing the RyR to Ca(2+), augments the Ca(2+) response (calcium-induced calcium release) initiated by activation of the IP(3)R.

CD38 Mediates Angiotensin II–Induced Intracellular Ca2+ Release in Rat Pulmonary Arterial Smooth Muscle Cells

“…Inhibition of CD38 with NA, or inhibition of the cADPR and NAADP pathways, in the presence of the NOX inhibitors or ROS scavenger did not further suppress AICR. These observations are consistent with reports in renal afferent arterioles and cardiac myocytes that Ang II stimulates NOX to generate ROS, leading to enhanced ADP-ribosyl cyclase activity (36,44).…”

“…This result suggests that the contribution of CD38 to the physiological functions of various vasculatures may be different. Vascular functions of CD38 have not been examined in cerebral arteries despite the abundance of expression, but they are well characterized in renal arteries and arterioles (10,11,14,34,36). It has been shown that CD38-dependent pathways modulate cytosolic [Ca 21 ] i and contractile functions in renal afferent arteries and arterioles and can account for 50% of the contractile response to Ang II, ET-1, and norepinephrine (10).…”

Involvement of neutral sphingomyelinase in the angiotensin II signaling pathway

“…Therefore, sphingosine is not involved in the renal vasoconstriction stimulated by either ANG II or nSMase. However, it has been reported that OEA causes vasorelaxation partly via an endothelium-dependent mechanism (14). More recently, attention has turned to a possible role of COX metabolites in the OEA actions in the vasculature (49).…”

“…In cases in which NO production is significantly decreased and/or reactive oxygen species (ROS) levels are increased, the activation of RhoA/Rho-kinase may contribute to increased vascular tone (29,30,52). Furthermore, Src-dependent pathways and nicotinic acid adenine dinucleotide phosphate (NAADP), another second messenger generated by the enzyme ADP-ribosyl (ADPR) cyclase, may contribute to the Ca 2ϩ signaling of ANG II (8,13,14,29,30). Furthermore, to support the hypothesis that the ANG II/AT 1 receptor/nSMase/ceramide-PLA 2 /TxA 2 pathway contributes to the regulation of renal vasoconstriction, we demonstrated the expression of nSMase, ceramide, and cPLA 2 in the smooth muscle layer of intrarenal vessels.…”

Adrenomedullin and Angiotensin II in Rat Cerebellar Vermis: Reactive Oxygen Species Production

“…In particular, ANG II-induced hypertrophy is inhibited by over-expression of CAT, or by inhibition of vascular NAD(P)H oxidase [41,42]. It is well established that ROS are important intracellular messengers of many physiological and pathological effects of circulating ANG II, since they are blocked by apocynin, a NAD(P)H oxidase inhibitor [43] or by CAT over-expression [28,41]. In addition, ANG II has been shown to stimulate the increase of both monocyte chemotactic protein 1 (MCP-1) and vascular cell adhesion protein 1 (VCAM-1) mRNA expression in rat aorta.…”