IGF-1–induced lipid accumulation impairs mesangial cell migration and contractile function

Abstract

Chronic treatment of mesangial cells with insulin-like growth factor-1 (IGF-1) results in intracellular lipid accumulation. These mesangial cells resemble foam cells. To determine whether this phenotype affects cell function, lipid-laden mesangial cells were tested for their ability to migrate in response to IGF-binding protein-5 (IGFBP-5) and to contract in response to angiotensin II (Ang II). IGFBP-5 binding and subsequent activation of the signal transduction cascade for migration were examined. To confirm that lipid accumulation was responsible for impaired contractility, lipid was removed from lipid-laden mesangial cells and the cells were re-tested for contractile response to Ang II. In comparison to control mesangial cells, lipid-laden cells failed to migrate in response to IGFBP-5. Although cellular binding of IGFBP-5 was not altered by lipid accumulation, IGFBP-5 failed to activate cdc42, a Rho GTPase required for IGFBP-5-mediated mesangial cell migration. These data indicate that lipid accumulation within the mesangial cell interferes with the signal transduction response to IGFBP-5. In addition, mesangial cells treated with IGF-1 had reduced contraction to Ang II. When lipid accumulation was exaggerated by adding cholesteryl esters to the culture medium, mesangial cells failed to contract in response to Ang II. Following removal of excess lipid from these mesangial cells, the contractile response to Ang II was restored. IGF-1 induces lipid accumulation in mesangial cells, which impairs their ability to respond to specific migratory and contractile stimuli. These observations are relevant to understanding functional abnormalities in diseases where mesangial foam cells occur, such as focal and segmental glomerulosclerosis and diabetic nephropathy.