Abstract
Insulin-like growth factor (IGF)/IGF binding protein (IGFBP) abnormalities may be important in the pathogenesis of growth failure in chronic renal failure (CRF). We induced experimental CRF by 5/6 nephrectomy in Sprague Dawley rats (100 g) and observed for 2 weeks comparing with sham-operated pair-fed control rats (Sham- C). CRF rats gained 30% less height than Sham- C rats (P < 0.01). Serum IGFBP profiles by Western ligand blot revealed that IGFBP4 was elevated two fold in CRF rats (P < 0.01 vs. Sham-C). However, IGFBP4 mRNA levels in liver or skeletal muscle were not different in two groups. To determine if the increase of serum IGFBP4 in CRF retarded the growth of cartilage, epiphyseal chondrocytes were isolated from CRF or control rats and cultured in the presence of control or CRF rat sera. Incubation with 10% CRF serum reduced proliferations of normal chondrocytes and L6 rat skeletal muscle cells. In contrast, 10% CRF serum did not inhibit the growth of CRF chondrocytes. Rat sera from two groups were separated into two different fractions, high (>10 kDa, containing IGFBPs) and low (<10 kDa, containing free IGF) molecular weight fractions using a gel filtration column. Both fractions obtained from CRF sera decreased the growth of control chondrocytes up to 40% compared with those from control sera. We suggest that the pathogenesis of growth failure in CRF may be involved in the increase of circulating IGFBP4 as well as the unidentified small molecular weight uremic serum factors which block the growth of chondrocytes in growth plate.
Highlights
Growth retardation is a serious problem found in children with chronic renal failure (CRF)
Maintenance of the serum growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis is thought to be important in normal growth, and alteration of this axis is considered as one of the factors for the growth impairment in CRF (Tonshoff et al, 1990)
Serum Insulin-like growth factor (IGF)-I and IGF-II levels were slightly decreased and IGF binding protein (IGFBP) levels were increased in CRF patient sera possibly due to the reduced renal clearance (Mehls et al, 1992)
Summary
Growth retardation is a serious problem found in children with chronic renal failure (CRF). Maintenance of the serum GH/IGF-I axis is thought to be important in normal growth, and alteration of this axis is considered as one of the factors for the growth impairment in CRF (Tonshoff et al, 1990). Plasma level of GHBP was increased and GH receptor level in liver was decreased in CRF, which might be causes of GH resistance. Serum IGF-I and IGF-II levels were slightly decreased and IGFBP levels were increased in CRF patient sera possibly due to the reduced renal clearance (Mehls et al, 1992). Increase of serum IGFBPs could reduce the bioavailability of free IGF resulting in growth impairment in CRF (Richmond et al, 2001). The effects of the CRF and control sera on the growth of rat epiphyseal chondrocytes were studied. The results could provide us a direct evidence for the inhibitory effects of serum components on the growth of growth plate chondrocytes
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