An important concept that has emerged in diabetes research is the idea that AngII not only mediates intraglomerular hypertension but also behaves as a growth factor that causes some of the hypertrophy and fibrosis seen in diabetic renal disease (reviewed in ). Much of the latter effect of AngII appears to be mediated by TGF-P. Tissue culture studies have demonstrated that AngII stimulates TGF-P1 production in proximal tubular cells  and mesangial cells . AngII also stimulates the biosynthesis of matrix by cultured renal cells [97-99]. This appears to be mediated by the TGF-P system because various anti-TGF-P regimens have abolished the AngII-induced increases in collagen I, collagen IV, and fibronectin [96, 99-101].
AngII has also been shown to cause hypertrophy in both proximal tubule cells and mesangial cells [97, 102-104]. This mechanism of action is most likely mediated by TGF-P since neutralizing anti-TGF-P antibodies ameliorates the hypertrophic effects [38, 105, 106]. Thus, the antifibrotic and anti-hypertrophic effects of angiotensin blockade are partly related to its ability to reduce TGF-P overexpression in the kidney. This viewpoint may help explain the renoprotective effects of the angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) [94, 107], in addition to their well-accepted hemodynamic benefits . Indeed, ACE inhibitors or ARBs decrease the intrarenal levels of TGF-P 1, both in animal models of diabetes and in human diabetes.[109-113] These data suggest that TGF-P can mediate the hypertrophic and sclerotic effects of AngII, offering angiotensin blockade as another modality to combat TGF-P associated disease.
Clinical conditions that are associated with upregulation of the renin-angiotensin system often upregulate TGF-P expression. For example, a high intraglomerular hydrostatic pressure secondary to efferent arteriolar constriction by AngII stretches the mesangial cell and stimulates it to produce TGF-P isoforms . That AngII increases TGF-P can also be seen in the unilateral ureteral obstruction (UUO) model of tubulointerstitial fibrosis. UUO was performed in a group of transgenic mice that express different numbers of angiotensinogen genes (zero to four copies). As expected, the number of genes determined the tissue levels of AngII in a graded fashion. More remarkably, the number of angiotensinogen genes increased linearly with the levels of TGF-fi mRNA in the obstructed kidney, and mice with no angiotensinogen genes had TGF-fi expression levels similar to those of non-obstructed control animals . This study supports the idea that angiotensin availability regulates the extent of TGF-fi transcription.
Human studies further support the interaction of AngII and TGF-fi. A subanalysis of The Collaborative Study Group Captopril Trial demonstrated that treatment with captopril correlated with the reduction of serum TGF-fi1 levels . There was a significant decrease of 21% in serum TGF-fi1 levels in the captopril-treated group after 6 months, while there was a slight increase of 11% in the placebo group after the same period. The decrease in serum TGF-fi1 levels in the captopril group correlated with stabilization of the glomerular filtration rate over the ensuing 2-year period, and this association was even more pronounced in the subset of patients with an initial glomerular filtration rate of less than 75 ml/min. Further, the addition of an ARB to maximal ACE inhibitor therapy was able to suppress urinary TGF-fi 1 levels even more than the ACE inhibitor alone, suggesting that more comprehensive blockade of the renin-angiotensin system would confer extra renoprotection .
The polypeptide endothelin-1 (ET-1) appears to have important links to AngII and TGF-fi. When either AngII or ET-1 was injected into transgenic mice that express the reporter gene luciferase under the control of the collagen type I promoter, the mRNA expression of collagen I was increased in the aorta and renal cortex . The increase in collagen I induced by AngII was inhibited by the administration of an endothelin receptor antagonist, bosentan. In addition, the AngII-stimulated collagen I was also blocked by a TGF-fi scavenger, decorin. These data indicate that AngII can activate the collagen I gene in the renal cortex by a mechanism requiring the participation or cooperation of ET and TGF-fi .
Studies on diabetic models showed that glomerular expression of ET-1 mRNA is increased in STZ-diabetic rats  and the urinary level of ET-1 is elevated in the diabetic BB rat . Moreover, an endothelin receptor A antagonist,
FR13 9317, given to STZ-diabetic rats attenuated glomerular hyperfiltration and urinary protein excretion and decreased glomerular mRNA levels of collagens, laminins, tumor necrosis factor (TNF-a), PDGF-B, TGF-^1, and basic fibroblast growth factor (bFGF) .
In humans, studies show that type 2 diabetic patients exhibit higher endothelin levels than the general population . Among the type 2 diabetic patients, those with retinopathy have even higher levels of endothelin. In another study of type 2 diabetes, treatment with captopril reduces circulating ET-1 levels , again suggesting a role for AngII in the upregulation of ET-1 in diabetes.
Studies in experimental animal models have demonstrated increased renal thromboxane expression  and urinary excretion of thromboxane B2 shortly after the onset of diabetes [122-124]. The source of increased thromboxane production may be the diabetic glomerulus  and/or infiltrating platelets . Addition of thromboxane analogs to mesangial cells in culture results in stimulation of fibronectin production  that appears to be mediated by PKC activation . Inhibitors of thromboxane synthesis and its receptor have been found to ameliorate diabetes-induced albuminuria [125, 129] and mesangial matrix expansion , but they may not prevent thickening of the GBM [125, 130]. Thromboxane may also exert a hemodynamic effect on the glomerulus via AngII. Thromboxane inhibitors administered to normoglycemic or STZ-induced diabetic Wistar Kyoto (WKY) rats reduced the AngII-induced increase in perfusion pressure .
It should be noted that exogenous prostaglandin E2 (PGE2) or drugs capable of increasing endogenous PGE2 dose-dependently decrease the level of extracellular matrix protein and mRNA and also dampen TGF-P gene expression in cultured rat mesangial cells . In streptozotocin-diabetic rats, an antagonist of the prostaglandin receptor EP1 inhibited TGF-P transcription and the expression of fibronectin. In terms of histologic and clinical benefits, the prostaglandin inhibitor ameliorated renal hypertrophy, decreased mesangial expansion, and completely suppressed proteinuria .
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