Elevated myocardial cytosolic calcium impairs insulin-like growth factor-1-stimulated protein synthesis in chronic renal failure.
Rats and humans with chronic renal failure (CRF) are reported to have resistance to recombinant human insulin-like growth factor-1 (rhIGF-1). Because basal cytosolic calcium ([Ca2+]i), a second messenger, may be increased in CRF, this study was conducted to examine whether elevated basal [Ca2+]i may cause resistance to IGF-1. Cardiomyocytes from four groups of rats were studied: untreated CRF, CRF with parathyroidectomy (PTX), CRF with the calcium channel blocker felodipine (F), and sham operation of the kidney (SO). CRF was created by ligation of two-thirds of the left renal artery and contralateral nephrectomy. Rats from each group were pair-fed the same diet for 20 to 22 d. Basal [Ca2+]i in cardiomyocytes (nM) in the CRF rats (102.0 +/- 2.8; SEM), was significantly higher than in each of the CRF-PTX, CRF-F, and SO groups (65.2 +/- 1.9, 63.8 +/- 2.6, and 63.5 +/- 2.0, respectively; P < 0.01). rhIGF-1 increased cardiomyocyte [Ca2+]i in all four groups of rats. The rise in [Ca2+]i was significantly diminished in the CRF rats (P < 0.05) and did not differ among the CRF-PTX, CRF-F, and SO rats. Protein synthesis after incubation with 0, 50, 100, 200, or 400 ng/ml rhIGF-1 was lower in cardiomyocytes from CRF rats than in each of the other three groups (P < 0.05) and was significantly less in the CRF-F rats compared with SO animals. IGF-1 receptor mRNA and IGF-1 receptor number and affinity were not different among the four groups. These findings suggest that cardiomyocytes from CRF rats display elevated basal [Ca2+]i and attenuated rhIGF-1-induced increase in [Ca2+]i; basal protein synthesis is decreased, and IGF-1-stimulated protein synthesis is impaired; elevated basal [Ca2+]i seems to contribute to this diminished response to rhIGF-1.
Qing
D P
DP
Department of Medicine, Harbor-UCLA Medical Center, Torrance, California 90509, USA.
Ding
H
H
Vadgama
J
J
Wu
Y Y
YY
Kopple
J D
JD
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D016105:Parathyroidectomy; D014176:Protein Biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000032:analysis
D002121:Calcium Channel Blockers; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D002118:Calcium