Molecular mechanism of ADP-ribosyl cyclase activation in angiotensin II signaling in murine mesangial cells

Abstract

ribosyl cyclase (ADPR-cyclase) produces a Ca 2ϩ -mobilizing second messenger cyclic ADP-ribose (cADPR) from NAD ϩ . In this study, we investigated the molecular basis of ADPR-cyclase activation and the following cellular events in angiotensin II (ANG II) signaling in mouse mesangial cells (MMCs) signal, but not the transient Ca 2ϩ signal, was blocked by a cADPR antagonistic analog, 8-bromo-cADPR (8-Br-cADPR), and an ADPRcyclase inhibitor, 4,4Ј-dihydroxyazobenzene (DHAB). In support of the results, ANG II stimulated cADPR production in a time-dependent manner, and DHAB inhibited ANG II-induced cADPR production. Application of pharmacological inhibitors revealed that activation of ADPR-cyclase by ANG II involved ANG II type 1 receptor, phosphoinositide 3-kinase, protein tyrosine kinase, and phospolipase C-␥1. Moreover, DHAB as well as 8-Br-cADPR abrogated ANG II-mediated Akt phosphorylation, nuclear translocation of nuclear factor of activated T cell, and uptake of [ 3 H]thymidine and [ 3 H]leucine in MMCs. These results demonstrate that ADPR-cyclase in MMCs plays a pivotal role in ANG II signaling for cell proliferation and protein synthesis.

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

“…CD38 expression has been reported in some systemic arteries, including aorta and the coronary and renal arteries (8)(9)(10). Endogenous vasoconstrictors, such as norepinephrine, endothelin-1 (ET-1), and angiotensin II (Ang II), have been shown to activate the cyclase and catalase activities of CD38, contributing to the elevation of [Ca 21 ] i and vasoconstriction (11)(12)(13)(14)(15)(16). In general, these vasoconstrictory agonists of G-protein-coupled receptors activate phospholipase C (PLC) to synthesize inositol trisphosphate (IP 3 ) and diacyglycerol from phosphatidylinositol bisphosphate.…”

Role of kidney ADP-ribosyl cyclase in diabetic nephropathy

“…Several reports indicate that interruption of the renin-angiotensin system (RAS), using the ANG II type 1 receptor (AT1R) blocker or an angiotensin-converting enzyme inhibitor, is clinically effective in slowing the decline of renal function in several nephropathies, including DN (3,10,19). These data support the notion that ANG II can worsen DN.ADP-ribosyl cyclase(s) (ADPR-cyclase) are regulated through G protein-coupled receptor signaling, including the receptor for ANG II (9,11,16,28). The product of ADPR-cyclase, cADPribose (cADPR), modulates Ca 2ϩ fluxes in several types of cells (6, 9, 11).…”

Kidney ADP-Ribosyl Cyclase Inhibitors as a Therapeutic Tool for Diabetic Nephropathy

“…Ang II signaling pathway (adopted from [4]). Stimulation of AT1R by Ang II leads to sequential activation of PI3K, PTK, and PLC1, in turn causing a Ca 2+ release by IP 3 R from ER, resulting in activation of ADPRcyclase.…”

“…Mounting evidence has indicated that G protein-coupled receptors, including the angiotensin II (Ang II) receptor, mediate activation of ADPR-cyclase to generate Ca 2+ signaling messengers (3)(4)(5). We have studied Ang II receptor-mediated activation of ADPR-cyclase, resulting in Ca 2+ dysfunction Fig.…”

“…www.intechopen.com which plays an important role in the pathogenesis of renal failure using an in vitro and an in vivo model (4,6). In this review article, I would like to give an overview on the current worldwide status of diabetic nephropathy (DN) as a leading cause of end-stage renal disease (ESDR), the causative role of renin-angiotensin-aldosterone system (RAAS) for DN, the role of ADPR-cyclase in pathogenesis of DN and a potential therapeutic tool for DN by the intervention of Ang II receptor-mediated Ca 2+ signaling with a kidney-specific ADPR-cyclase inhibitor.…”