Vasoactive humoral factors such as AngII, endothelins, and altered prostaglandin metabolism have all been implicated in the pathogenesis of diabetic nephropathy, and all these factors may upregulate the TGF-P/TGF-P receptor system in the diabetic kidney (reviewed in [7, 18]). AngII is capable of stimulating TGF-P production in proximal tubular and mesangial cell cultures [95, 96]. Hyperglycemia acts in synergy with locally increased AngII to stimulate renal hypertrophy and synthesis of extracellular matrix proteins (reviewed in ). In return, AngII can potentiate the effects of high glucose by inhibiting proteinases responsible for protein turnover and stimulating TGF-P synthesis . Moreover, hyperglycemia can enhance the expression of AngII-receptors and prolong the half-life of AngII itself by inhibiting the enzymes that would degrade AngII. The net effect, therefore, is increased bioactivity of AngII.
As reviewed above, endothelins may stimulate TGF-P production because endothelin receptor antagonists decrease the overexpression of glomerular TGF-P1 mRNA in diabetic rats . Thromboxane has also been demonstrated to stimulate TGF-P production in mesangial cells .
The stimulus for chronic upregulation of TGF-P may be partly related to the presence of glycated proteins in long-standing diabetes [190, 191]. The early Amadori-glucose adducts of proteins such as serum albumin have been shown to stimulate TGF-P expression in mesangial cells and glomerular endothelial cells [191, 192]. Administration of AGE-modified proteins to normal mice elevates the mRNA levels of TGF-P1, a1(IV) collagen, and laminin B1. These increases are reversed by concomitant aminoguanidine therapy . Exposure to glycated LDL increases TGF-P1 and fibronectin mRNA levels in cultured murine mesangial cells . The increased fibronectin message is prevented by anti-TGF-P antibody treatment . Finally, mesangial cells have specific receptors for AGE which may result in enhanced matrix and cytokine production [143, 195].
In addition to the metabolic factors listed above, hemodynamic and mechanical forces are operative in the diabetic state. The cyclical stretch/relaxation of mesangial cells in culture, which closely mimics increased glomerular pressure in vivo [114, 196, 197], has been associated with increased synthesis of TGF-P and extracellular matrix molecules. Fluid shear stress increases message expression and synthesis of the active form of TGF-P in cultured bovine aortic endothelial cells .
The link between oxidative stress and TGF-P is gaining increasing attention in mediating diabetic renal injury. Oxidative stress, generated by glucose metabolism and advanced glycation end-products (AGEs), can trigger a multitude of pathogenetic mechanisms that collectively contribute to the microvascular complications of diabetes . A major component of oxidative stress, the reactive oxygen species (ROS), may act through the TGF-P pathway to exert a profibrotic effect. To generate ROS under experimental conditions, investigators have used glucose oxidase (GO), an enzyme that continuously catalyzes ambient glucose to hydrogen peroxide. The addition of GO to human mesangial cells in culture stimulates the promoter activity, mRNA level, bioactivity, and protein production of TGF-P1 . GO also increases the gene expression of several extracellular matrix proteins, including collagen types I, III, and IV, and fibronectin. However, this GO-stimulated expression of matrix was prevented by a panselective, neutralizing anti-TGF-fi antibody . Thus, the reactive oxygen species may exert their deleterious effects on kidney cells via the TGF-fi system.
Oxidative stress has also been shown to activate the protein kinase C (PKC) pathway. Recent data have demonstrated that inhibition of high glucose-induced PKC activation effectively abrogates reactive oxygen species generation and nuclear factor-KB (NF-kB) activity, decreasing monocyte chemoattractant protein-1 secretion in mesangial cells . Transcription factors such as NF-kB enhance the transactivation of genes encoding cytokines like TGF-fi and the related Connective Tissue Growth Factor (CTGF) that up-regulate extracellular matrix expression [200, 202]. Taken together, evidence is accumulating to suggest that the different biochemical abnormalities produced by hyperglycemia can influence one another, since many of the glucose metabolites serve as important intermediates for the different metabolic pathways.
Upregulation of the renal type II TGF-fi receptor in the diabetic state represents another major pathway for enhanced bioactivity of the TGF-fi system. Type 1 diabetes in the STZ-induced mouse model increases the quantity of type II receptor at both the mRNA and protein levels . In tissue culture, high ambient glucose  and Amadori glucose adducts of albumin  both increase the expression of the TGF-fi type II receptor by mesangial cells. Interestingly, captopril inhibits high glucose-mediated hypertrophy of tubular LLC-PK1 cells, perhaps by blunting the protein expression of the types I and II TGF-fi receptors . This illustrates that AngII can upregulate the TGF-fi system, also at the receptor level.
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