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 ([Ca 2+ ] i ), a second messenger, may be increased in CRF, this study was conducted to examine whether elevated basal [Ca 2+ ] 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 [Ca 2+ ] 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 [Ca 2+ ] i in all four groups of rats. The rise in [Ca 2+ ] 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 [Ca 2+ ] i and attenuated rhIGF-1-induced increase in [Ca 2+ ] i ; basal protein synthesis is decreased, and IGF-1-stimulated protein synthesis is impaired; elevated basal [Ca 2+ ] i seems to contribute to this diminished response to rhIGF-1.