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.

Circulating MicroRNAs Associate With Diabetic Nephropathy and Systemic Microvascular Damage and Normalize After Simultaneous Pancreas–Kidney Transplantation

“…As expected, we observed strong correlations for the levels of circulating miRNAs with circulating parameters of renal function (eGFR and creatinine) and DM (glucose and HbA1c). When relating the miRNA levels to markers of DN (IGF) (14), microvascular destabilization (Ang-2/Ang-1, MTI) and injury (sTM), strongest correlations were found for miR-130b with Ang-2/Ang-1 ratio (r ¼ 0.40, p < 0.001), miR223 with IGF (r ¼ À0.35, p < 0.001) and miR-326 (r ¼ 0.42, p < 0.001) and miR-660 (r ¼ 0.45, p < 0.001) with MTI. Finally we determined which of these miRNA associations with microvascular integrity were independent of kidney function and DM parameters.…”

Angiotensin II- and glucose-stimulated extracellular matrix production: mediation by the insulin-like growth factor (IGF) axis in a murine mesangial cell line

“…The kidney expresses all six IGFBPs, of which IGFBP-1 and IGFBP-2 have been observed to exhibit increased tissue levels during the onset of diabetic nephropathy [19,21,22,32,33,[43][44][45]. IGFBPs bind IGF peptides with high affinities and can modulate IGF localization to cellular targets and IGF receptor activation [46,47].…”

“…A mesangial IGF signaling system has also been implicated in diabetic glomerulosclerosis [17,[19][20][21][22]31,32]. Diabetic mesangial cells or cells cultured in high glucose express increased levels of IGF-I, enhanced IGF receptor expression and binding, and altered levels of IGFbinding proteins (IGFBPs) [18,21,[33][34][35].…”

“…These include the renin-angiotensin system (RAS); [10][11][12][13][14][15][16], the insulin-like growth factor (IGF) axis [17][18][19][20][21][22], and transforming growth factor-β1 (TGF-β1); [23][24][25][26]. Several studies to date have provided compelling support for the existence of an independent mesangial cell RAS whose activation appears to be critical in the development of diabetic nephropathy [10,13,14,27,28].…”

Identification of MUP1 as a Regulator for Glucose and Lipid Metabolism in Mice

“…The liver secretes a variety of proteins, including insulin likegrowth factor-1 (IGF-1), insulin-like growth factor-binding proteins, fibroblast growth factor-21 (FGF-21) and major urinary proteins (MUPs) (2)(3)(4)(5)(6). Insulin-like growth factor-binding proteins and FGF-21 have been well documented to regulate multiple aspects of glucose and lipid metabolism in animals (2,3,7).…”