The role of the IGF axis in IGFBP-1 and IGF-I induced renal enlargement in Snell dwarf mice

Abstract

Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is generally believed to inhibit IGF action in the circulation. In contrast, IGFBP-1 has been reported to interact with cell surfaces and enhance IGF-I action locally in some tissues. Renal IGFBP-1 levels are found elevated in various conditions characterized by renal growth (e.g. diabetes mellitus, hypokalemia).To test whether IGFBP-1 is a renotropic factor, IGFBP-1 was administered alone or in combination with IGF-I to Snell dwarf mice, an in vivo model without compensatory feedback effects on growth hormone (GH) secretion. In three control groups of Snell dwarf mice, placebo, GH or IGF-I was administered. Compared with placebo, kidney weight increased in all treated groups, however, with different effects on kidney morphology. Administration of IGF-I, alone or in combination with IGFBP-1, tended to increase glomerular volume, while no changes were seen in the other groups. Administration of IGFBP-1 or IGFBP-1+IGF-I both caused dilatation of the thin limbs of Henle's loop, while GH or IGF-I administration had no visible effect. Furthermore, IGF-I administration resulted in an increased mean number of nuclei per cortical area and renal weight, whereas GH, IGF-I+IGFBP-1 or IGFBP-1 caused a decreased renal nuclei number.In situ hybridization and immunohistochemistry showed specific changes of the renal IGF system expression patterns in the different groups. Particularly, IGFBP-1 administration resulted in extensive changes in the mRNA expression of the renal IGF system, whereas the other administration regimen resulted in less prominent modifications. In contrast, administration of IGFBP-1 and IGFBP-1+IGF-I resulted in identical changes in the protein expression of the renal IGF system.Our results indicate that IGFBP-1, alone or in combination with IGF-I, demonstrated effects on the renal tubular system that differ from the effects of IGF-I.

The physiological and pathophysiological roles of the GH/IGF-axis in the kidney: Lessons from experimental rodent models

“…IGFBP-6 mRNA is weakly expressed in the mouse kidney, being undetectable in the adult kidney. Similar expression pattern of IGF system mRNA, mostly co-localizing with its protein, was observed in kidney of adult Snell dwarf mice [31]. Northern blot analysis revealed abundant expression of IGFBP-1 to -5, while IGFBP-6 could not be detected in the adult mouse kidney [8,19,21].…”

SGK1 as a determinant of kidney function and salt intake in response to mineralocorticoid excess

“…Thus SGK1 could participate in the regulation of kidney growth and glomerular permeability. SGK1 is activated by IGF-I, a hormone implicated in the regulation of cell proliferation and renal growth (4,13,16,17,23,25,38,55,60). Moreover, excessive SGK1 transcription has been observed in diabetic nephropathy (31,32) and glomerulonephritis (15).…”

Polymorphisms in igf-Binding Protein 1 Are Associated With Impaired Renal Function in Type 2 Diabetes

“…IGFBPs have also been implicated in the development of nephropathy in human and rodent models (3,4,(23)(24)(25)(26)30,32,33). Flyvbjerg et al (33) and Landau et al (31) reported that the growth hormone, the principle biological regulator of IGF-I secretion, enhances diabetes-related renal IGFBP-1 upregulation at the mRNA and protein levels and exacerbates diabetic renal hypertrophy in STZ rats.…”

“…Renal hypertrophy is an earlyonset feature of experimental diabetic nephropathy and is correlated with an increase in IGF-I and a transient spike in IGFBP-1. However, cortical regulation of the IGF effect is mediated by IGFBPs (3,4,[23][24][25][26][27]. Feldmann et al (27) reported lower free IGF-I levels but an elevated total IGF-1 level, strongly suggesting a modulatory role for IGFBPs in this process.…”