CHOLESTEROL, MACROPHAGES, AND GENE-EXPRESSION OF TGF-BETA-1 AND FIBRONECTIN DURING NEPHROSIS

Hypercholesterolemia aggravates experimental progressive glomerular injury. Evidence suggests the infiltrating glomerular macrophage (Mphi) is a potential effector mechanism for the noxious effects of hypercholesterolemia. Because transforming growth factor (TGF)-beta1 is secreted by activated Mphis and also stimulates fibronectin production by glomerular cells, we evaluated the,kinetics of gene expression for these moieties in glomeruli isolated from nephrotic rats at 3, 7, 11, and 42 days after the delivery of puromycin aminonucleoside (PA). We also assessed whether cholesterol feeding, which raises the glomerular Mphi number, alters the glomerular mRNA levels for TGF-beta1 and fibronectin. Glomerular mRNA levels for TGF-beta1 and fibronectin in nephrotic rats exhibited a biphasic temporal pattern, decreasing significantly below control at 3 and 7 days after PA but increasing significantly at 11 and 42 days after PA. The upregulated gene expression for TGF-beta1 and fibronectin at 11 days after PA temporally corresponded to the phase of mesangial Mphi infiltration in this model. Cholesterol feeding to both normal and nephrotic rats significantly increased glomerular TGF-beta1 and fibronectin mRNA levels at 11 days after PA. Immunohistochemical labeling for Mphis and intracellular TGF-beta1 demonstrated both mesangial and cortical interstitial localization with the TGF-beta1-positive cells possessing Mphi nuclear morphology. These findings identify a novel interaction between hypercholesterolemia, augmented glomerular Mphi accumulation, and upregulated glomerular TGF-beta1 and fibronectin gene expression. These perturbations within the acutely injured glomerulus constitute an early pathobiological determinant for the later development of mesangial matrix expansion and glomerulosclerosis.