Adriamycin impairs the contraction of mesangial cells through the inhibition of protein kinase C and intracellular calcium.
The effects of adriamycin on the contractile function of cultured mesangial cells were measured by the changes in planar surface area in response to treatment with agonists. Incubation of mesangial cells with adriamycin (0.2 microg/ml) for 24 h significantly decreased the contractile responses to the calcium channel activator BAY K 8644 (1 microM) and to the PKC activator PMA (1 microM). Intracellular calcium concentration ([Ca(2+)](i)), measured by changes in fura 2 levels in response to ATP (0.1 mM), was significantly inhibited in adriamycin-treated mesangial cells compared with control cells. In the absence of extracellular calcium, treatment with ionomycin (0.1 mM) or thapsigargin (10 microM) resulted in a significantly smaller increase in [Ca(2+)](i) in adriamycin-treated mesangial cells compared with control, suggesting an important role of the endoplasmic reticulum in the effects of adriamycin. Using PKC-specific antibodies, adriamycin significantly decreased the cytosolic and membranous fractions of PKC-alpha in mesangial cells to 75 +/- 6 and 70 +/- 12% of control, respectively. The PKC activity of mesangial cells was also significantly inhibited after incubation with adriamycin for 24 h. In conclusion, adriamycin induces hypocontractility of mesangial cells, which may mediate this effect by inhibiting PKC-alpha and [Ca(2+)](i).
Jin
Jong-Shiaw
JS
Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
Yao
Chen-Wen
CW
Chin
Ting-Yu
TY
Chueh
Sheau-Huei
SH
Lee
Wei-Hwa
WH
Chen
Ann
A
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects*; D007425:Intracellular Membranes / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D009994:Osmolar Concentration; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium