The growth hormone-insulin-like growth factor-I axis in chronic kidney disease

Abstract

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are important physiologic regulators of growth, body composition, and kidney function. Perturbations in the GH-IGF-I axis are responsible for many important complications seen in chronic kidney disease (CKD), such as growth retardation and cachectic wasting, as well as disease progression. Recent evidence suggests that CKD is characterized by abnormalities in GH and IGF-I signal transduction and the interaction of these pathways with those that involve other molecules such as ghrelin, myostatin, and the suppressor of cytokine signaling (SOCS) family. Further understanding of GH/IGF pathophysiology in CKD may lead to the development of therapeutic strategies for these devastating complications, which are associated with high rates of mortality and morbidity.

Fig. 1

The normal growth hormone (GH) and insulin-like growth factor-I (IGF-I) axis in modulating growth and body composition. The synthesis and release of GH from pituitary are modulated by the hypothalamic hormones such as GH-releasing hormone (GHRH) and somatostatin, which in turn are modulated by feedback (dashed lines) from blood GH and IGF-I levels. Ghrelin also stimulates the release of GH. Circulating GH acts on many organs to stimulate the production of IGF-I. Liver is the major source of blood IGF-I. Most of the circulating IGF-I is bound to IGF-binding protein-3 (IGFBP-3) in a ternary complex with acid-labile subunit (ALS). A smaller fraction of the total IGF-I is bound to the five other IGFBPs. A small fraction of the total IGF-I in blood is in a bioactive-free fraction. In the kidney, IGF-I increases renal plasma flow and glomerular filtration rate. GH also affects many organs such as cartilage.

Fig. 2

Deranged GH and IGF-I axis in chronic kidney disease (CKD). The GH/IGF-I axis in CKD is changed markedly compared with the normal axis, as illustrated in Fig.1. In CKD, the circulating levels of GH are not reduced while circulating levels IGF-I are decreased. Furthermore, there is reduced effectiveness of endogenous GH and IGF-I, which probably plays a major role in reducing linear bone growth. The reduced effectiveness of endogenous IGF-I is likely due to decreased levels of free, bioactive IGF-I as levels of circulating inhibitory IGFBP1, 2, 4 and 6 are increased. In addition, less IGF-I is circulating in the complex with ALS and IGF-BP3 as the result of increased proteolysis of IGF-BP3. In sum, these lead to decreased IGF-I receptor activation and a decreased feedback to the hypothalamus and pituitary. Low free IGF-I and high IGFBP levels probably contribute to a reduced renal function and lead to a reduced stature. The direct effects of GH on bone, which are not fully understood, also are blunted. Blunt-ended line represents inhibition.

Fig. 3

Molecular mechanism of myostatin in muscle mass regulation in CKD. Myostatin appears to induce muscle wasting independent of NF-κB pathway. Increased levels of myostatin blocks myogenesis by downregulating pax3 and myoD expression. In addition, myostatin upregulates proteolysis by phosphorylating FOXO1 through the inhibition of the PI3K/AKT signaling pathway. Blunt-ended line represents inhibition.

Fig. 4

Janus kinase (JAK), signal transducers and activators of the transcription (STAT) and suppressor of cytokine signaling (SOCS) pathways in CKD. Binding of GH to the GH receptor activates JAK2, which in turn activates downstream signaling pathway, including STAT1, 3, 5a and 5b. The phosphorylated STATs dimerize, translocate into the nucleus and bind to specific DNA sequences and induce target genes including SOCS. In turn, these SOCS proteins inhibit JAK/STAT signal transduction, forming a negative feedback loop. The SOCS proteins bind to the phosphorylated receptors or JAKs and inhibit signal transduction by suppressing JAK activity or by competing with the STATs for receptor docking sites or by targeting the interacting signaling proteins for proteasomal degradation. Growth retardation and muscle wasting in CKD may arise through several mechanisms such as decreased phosphorylation of the GHR, JAK2, and STAT5 in liver and muscle. Nuclear translocation of phosphorylated STAT5 is reduced. As STAT5b is essential for the transcription of IGF-I and IGF-I is an important stimulator of body growth, this signaling defect may presumably contribute to the impaired GH-induced body growth retardation and muscle wasting in CKD. One mechanism that may contribute to the impaired JAK2-STAT phosphorylation involves the SOCS molecules. In CKD, levels of hepatic SOCS2 and SOCS3 and in muscle SOCS2 mRNA are increased. Blunt-ended line represents inhibition.