Essential role of Ca2+ release channels in angiotensin II-induced Ca2+ oscillations and mesangial cell contraction.
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.
Feng
Z
Z
Department of Nephrology, Kidney Center and Key Lab of PLA, Chinese General Hospital of PLA, Beijing, China.
Wei
C
C
Chen
X
X
Wang
J
J
Cheng
H
H
Zhang
X
X
Hong
Q
Q
Shi
S
S
Fu
B
B
Wei
R
R
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D015220:Calcium Channels / Q000032:analysis / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008297:Male; D050527:Mesangial Cells / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D018613:Microscopy, Confocal; D009119:Muscle Contraction; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000032:analysis / Q000187:drug effects / Q000502:physiology*
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D019837:Ryanodine Receptor Calcium Release Channel; D000804:Angiotensin II; D002118:Calcium