Essential role of Ca2+ release channels in angiotensin II-induced Ca2+ oscillations and mesangial cell contraction

Abstract

The increased resistance of the glomerulus as a result of contractile dysfunction of mesangial cells (MCs) is associated with reduction of glomerular filtration rate and development of glomerulosclerosis. Evidences show MCs contraction changes with intracellular Ca(2+) concentration ([Ca(2+)](i)). Here, we explore the mechanism of angiotensin II (AngII)-induced Ca(2+) oscillations and MCs contraction. Primary MCs from 3-month-old and 28-month-old rats were used for detection of Ca(2+) oscillations and MC planar area with confocal microscopy. AngII could induce typical Ca(2+) oscillations and contraction of MCs. This process was abolished by thapsigargin, 2-aminoethoxydiphenyl borate, or 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphorylcholine, and partially inhibited by ryanodine, but could not be inhibited in the absence of extracellular Ca(2+). Ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate (InsP(3)) receptors displayed a strong colocalization, which may contribute to the amplification of Ca(2+) response. MLC(20) phosphorylation and MC planar area were associated with AngII-induced Ca(2+) oscillations. The frequency of Ca(2+) oscillations was dependent on the AngII concentration and correlated with the MCs' contractive extent, which could be attenuated by KN-93. The amplitude reduction of oscillations correlated with the decrease in aging-related contraction. In conclusion, [Ca(2+)](i) response of MCs to AngII is characterized by repetitive spikes through the following repetitive cycles: Ca(2+) release by phospholipase C -InsP(3) pathway, Ca(2+) amplification by Ca(2+)-activated RyRs and Ca(2+) reuptake by the endoplasmic reticulum. MCs contraction can be modulated by oscillations not only in an AngII-induced frequency-dependent mode but also in an aging-related, amplitude-dependent mode.

Membrane current oscillations in descending vasa recta pericytes

“…8), pointing to a role for Ca 2ϩ release from RyR-sensitive stores in their generation. This is similar to findings in other preparations (13,19,24,32). 2-APB is frequently used to inhibit IP 3 receptors but is known to have other effects, particularly to block store-operated cation channels.…”

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

“…However, except for IL-8-mediated CD38 activation in lymphokine-activated killer (LAK) cells (29), the molecular mechanism of ADPR-cyclase activation by other GPCRs has not been clarified. The major renin-angiotensin system effector, ANG II, plays critical roles in cell growth, vascular contraction, migration, and salt water retention (1,7,21). Effects of ANG II are mediated by at least two structurally and pharmacologically distinct ANG II type 1 and 2 receptors (AT 1 R and AT 2 R, respectively) (7,21).…”

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

“…Effects of Ang II are mediated by at least two structurally and pharmacologically distinct Ang II type 1 and 2 receptors (AT1R and AT2R, respectively) (23,24). The physiological and pathophysiological effects of Ang II are mainly exerted by AT1R activation (24)(25)(26) via complex interacting signaling pathways involving the primary stimulation of phospholipase C (PLC) and Ca 2+ mobilization and the secondary activation of protein tyrosine kinase (PTK), extracellular signal-regulated kinases-1 and -2, and phosphatidylinositol 3-kinase (PI3K)-dependent kinase Akt (23)(24)(25)(26). We extended these signaling pathways mainly focusing on the molecular basis of Ca 2+ signaling by ADPR-cyclase activation in Ang II signaling in murine mesangial cells (MMCs) and other cells (see below).…”

“…The final step of the RAAS cascade is the activation of Ang II receptors by Ang II. In the kidney, Ang II plays critical roles in the regulation of the glomerular filtration rate (GFR) and renal blood flow, and salt water retention (22)(23)(24). Effects of Ang II are mediated by at least two structurally and pharmacologically distinct Ang II type 1 and 2 receptors (AT1R and AT2R, respectively) (23,24).…”

“…In the kidney, Ang II plays critical roles in the regulation of the glomerular filtration rate (GFR) and renal blood flow, and salt water retention (22)(23)(24). Effects of Ang II are mediated by at least two structurally and pharmacologically distinct Ang II type 1 and 2 receptors (AT1R and AT2R, respectively) (23,24). The physiological and pathophysiological effects of Ang II are mainly exerted by AT1R activation (24)(25)(26) via complex interacting signaling pathways involving the primary stimulation of phospholipase C (PLC) and Ca 2+ mobilization and the secondary activation of protein tyrosine kinase (PTK), extracellular signal-regulated kinases-1 and -2, and phosphatidylinositol 3-kinase (PI3K)-dependent kinase Akt (23)(24)(25)(26).…”