Other Mediators In Diabetic Renal Disease AngII

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 [94]). 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 [95] and mesangial cells [96]. 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 [108]. 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 [114]. 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 [115]. 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 [89]. 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 [116].


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 [100]. 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 [100].

Studies on diabetic models showed that glomerular expression of ET-1 mRNA is increased in STZ-diabetic rats [117] and the urinary level of ET-1 is elevated in the diabetic BB rat [117]. 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) [118].

In humans, studies show that type 2 diabetic patients exhibit higher endothelin levels than the general population [119]. 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 [120], again suggesting a role for AngII in the upregulation of ET-1 in diabetes.

Thromboxane and prostaglandin

Studies in experimental animal models have demonstrated increased renal thromboxane expression [121] 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 [125] and/or infiltrating platelets [126]. Addition of thromboxane analogs to mesangial cells in culture results in stimulation of fibronectin production [127] that appears to be mediated by PKC activation [128]. Inhibitors of thromboxane synthesis and its receptor have been found to ameliorate diabetes-induced albuminuria [125, 129] and mesangial matrix expansion [125], 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 [131].

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 [132]. 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 [133].

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