Extracellular Matrix Accumulation
Extracellular Matrix Accumulation
A major feature of diabetic complications is extracellular matrix (ECM) accumulation. Although ECM was originally viewed to be essentially inert, it has now been shown not only to have a structural role but also to be in
a dynamic interaction with the surrounding cell population as well as being a reservoir for various cytokines and growth factors. ECM consists of structural proteins such as type IV collagen, cell-associated adhesion molecules such as the integrins, antiadhesins and growth factors. The role of all these proteins and their interactions in the genesis and progression of diabetic complications is now an area of intensive investigation. There are major changes in gene and protein expression of various ECM components in various sites of dia- a dynamic interaction with the surrounding cell population as well as being a reservoir for various cytokines and growth factors. ECM consists of structural proteins such as type IV collagen, cell-associated adhesion molecules such as the integrins, antiadhesins and growth factors. The role of all these proteins and their interactions in the genesis and progression of diabetic complications is now an area of intensive investigation. There are major changes in gene and protein expression of various ECM components in various sites of dia-
Transforming Growth Factor-b Transforming growth factor-b (TGF-b) has been shown to play a pivotal
role in ECM accumulation in the diabetic kidney. Renal expression of this cytokine has been reported to be increased in both experimental and human diabetes. Administration of antibodies to TGF-b prevents diabetes-associated renal hypertrophy. The role of this growth factor is further suggested by both in vitro and in vivo findings indicating that putative mediators of DN such as AII and AGEs promote expression of this cytokine. AII has been shown in vitro to promote collagen IV production via TGF-b in mesangial cells. In the model of subtotal nephrectomy, an animal model of progressive renal injury with many hemodynamic and structural similarities to diabetes, it has been shown that in vivo inhibition of the action of AII, either by ACE inhibition or by AII receptor antagonism, is associated with reduced gene expression of
TGF-b 1 . These treatments lead not only to reduced ECM accumulation but attenuation of glomerular and tubulointerstitial injury and preservation of renal function. More recently, a similar phenomenon has been observed in
experimental diabetes with reduced TGF-b 1 gene expression after ACE inhibi- tion, particularly in the tubulointerstitium. Reduced TGF-b 1 expression after ACE inhibition has also been observed in vessels from diabetic rodents. Exogenous administration of AGEs upregulates a range of cytokines including TGF-b in the kidney. Recent studies have explored the relationship between TGF-b 1 , collagen and AGEs in diabetic vessels and shown that the increase in gene expression of TGF-b 1 in diabetic vessels can be prevented by administration of the inhibitor of advanced glycation, aminoguanidine. Recent studies suggest that these effects of inhibitors of glycation on growth factor and structural protein expression are also observed in the diabetic kidney. At this stage, no specific inhibitors of cytokine formation or action are available for clinical use. Therefore, the major strategy for preventing renal TGF-b overexpression is via inhibition of stimuli of secretion of this prosclerotic cytokine (fig. 1).