Novel roles of the IGF–IGFBP axis in etiopathophysiology of diabetic nephropathy

Abstract 

Mechanisms contributing to development of diabetic nephropathy (DN) remain unclear. High ambient glucose level transforms intracellular pathways, promoting stable phenotypic changes in the glomerulus such as mesangial cell hypertrophy, podocyte apoptosis, and matrix expansion. Insulin-like growth factors (IGFs) and the high affinity IGF binding proteins (IGFBPs) exert major effects on cell growth and metabolism. Compared with diabetic patients without microalbuminuria (MA), MA diabetic patients display perturbed GH–IGF–IGFBP homeostasis, including increased circulating IGF-I and IGFBP-3 protease activity, increased excretion of bioactive GH, IGF-I, and IGFBP-3, but decreased circulating IGFBP-3 levels. In diabetic animal models, expression of IGF-I and IGFBP-1 to -4 increases in key renal tissues and glomerular ulrafiltrate. Epithelial, mesangial, and endothelial cells derived from the kidney respond to IGF-I binding with increased protein synthesis, migration, and proliferation. This article reviews classic and emerging concepts for the roles of the GH–IGF–IGFBP axis in the etiopathophysiology, treatment, and prevention of diabetic renal disease. We report IGF-independent actions of IGFBP-3 in the podocyte for the first time.

Abbreviations: ACEi, angiotensin-converting enzyme inhibitor, CTGF, connective tissue growth factor, DN, diabetic nephropathy, 4E-BP1, eukaryotic initiation factor 4E-binding protein, ecNOS, endothelial constitutive nitric oxide synthase, EGF, epidermal growth factor, eIF4E, eukaryotic initiation factor 4E, ESRD, end-stage renal disease, GH, growth hormone, IGF, insulin-like growth factor, IGFBP, IGF binding protein, IGFBP-rP, IGFBP related peptides, IGF-1R, Type 1 IGF receptors, MA, microalbuminuria, MAPK, mitogen-activated protein kinase, MC, mesangial cells, MDCK, Madin–Darby canine kidney cell line, NO, nitric oxide, NRK-49F cells, rat renal interstitial cells, PI 3 kinase, phosphatidylinositol 3-kinase, rhIGF-I, recombinant human insulin-like growth factor-I, Rho GTPase, Rho guanosine triphosphatases, SNAP, nitric oxide -donors S-nitroso-N-acetylpenicillamine, T2DM, type 2 diabetes mellitus, TGF-β, transforming growth factor-β, VEGF, vascular endothelial growth factor

Keywords: Diabetic nephropathy, IGF, IGFBPs, IGF receptor