Insulin-like growth factors (IGF) are a group of peptides that include insulin and relaxins with a common structural feature of three disulfide bonds linking a variable and a domain chain. Indeed, they were named for this reason, having been previously labeled as ‘somatomedins’ based on their purported biological activity as mediators of the growth hormone (GH, Somatotropin). The GH/IGF axis itself includes these two ligands (IGF-1 and IGF-2), two receptors (IGF receptors 1 and 2), and six high-affinity IGF binding proteins (IGFBP-1 through 7, which primarily inhibit IGF actions). Initially, the IGF were thought to be synthesized primarily in the liver, and responsible for normal somatic growth and development. In the last few decades it has been found that, among other organs, mesangial cells and podocytes also produce IGF-1. With that knowledge, it comes as no surprise that IGF have been implicated not only in normal kidney growth and development, but also in the pathogenesis of many kidney diseases, as explained in a thorough review by Bach and Hale in a recent AJKD article.
IGF and Normal Growth in Physiology
IGF has an important role in normal skeletal growth, and its deficiency is linked to a syndrome of dwarfism (along with some interesting anthropological speculation). IGF 1 and 2 are also required for normal metanephric development. Animal models, notably in knockout mice, show that IGF-1 deficiency results not only in lower weight, but also in smaller kidneys, lower nephron number, and decreased glomerular size. Conversely, transgenic mice overexpressing IGF-1 or 2 have enlarged kidneys. Given their principal role as inhibitors of IGF action, overexpression of the IGFBPs (1, 2, 3 and 5 in particular) not surprisingly results in smaller kidneys. Interestingly, IGF may also have a role in compensatory renal hypertrophy that occurs after unilateral nephrectomy; indeed the effects of Klotho may be partially mediated via its modulation of IGF-1. With respect to renal physiology, the increase in glomerular filtration rate (GFR) that occurs secondary to GH administration is also mediated by IGF-induced decrease in renal vascular resistance. In addition, GH/IGF-1 also have an anti-natriuretic effect (leading patients with acromegaly to volume expansion and hypertension), mediated via increased tubular sodium re-absorption. GH/IGF-1 also increase tubular phosphate re-absorption by increasing the TmPO4, which assists with bone formation during juvenile growth.
IGF and Kidney Disease
In diabetic nephropathy, the GH-IGF-1 axis plays an important role, as demonstrated in animal models by the amelioration of diabetic nephropathy with use of somatostatin analogues and protection of typical diabetic kidney damage in GH-receptor knockout models. The mechanism of IGF induced damage is probably mediated by its effects on mesangial cells, but also perhaps on podocytes. It is a complex interplay, with increased activation of the IGF receptors, down regulation of the IGFBPs, and increased IGF-1 synthesis. Secondly, in chronic kidney disease, decreased IGF-1 activity may partially explain why these patients are malnourished. Moreover, in children with CKD, GH resistance is another reason for stunted growth, but fortunately, this can be successfully overcome with recombinant GH therapy. In autosomal dominant polycystic kidney disease (PCKD), the epithelial cells lining the cysts show an increase in expression of members of the IGF-pathway; fortunately, treatment of children with autosomal recessive PCKD with GH therapy does not result in any deleterious effect on kidney function or volume.
Modulation of the GH/IGF Axis with Therapy
There are indeed many ways to modulate the GH-IGF axis: recombinant GH, octreotide, pegvisomant (a GH antagonist), recombinant IGF-1, IGF receptor inhibitors, and IGFBPs. However, given the systemic effects of the GH/IGF axis, one of the challenges is to deliver the right molecule to the precise site of action within the kidney. There has been some encouraging data in animal models, but translation into human studies is still awaited.
In this excellent overview, Bach and Hale summarize the physiology and pathophysiology of the IGF in relation to the kidney, and provide some recent advances in this field, including the role of IGF-1 in stem cell therapy.
Dr. Swapnil Hiremath