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Mechanisms through which bradykinin promotes glomerular injury in diabetes

Division of Endocrinology-Diabetes-Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina

Submitted 4 May 2004 ; accepted in final form 20 October 2004

In diabetes, mesangial cell proliferation and extracellular matrix expansion are critical components in the development of glomerulosclerosis. We reported that diabetes alters the activity of the kallikrein-kinin system and that these alterations contribute to the development of diabetic nephropathy. The present study examined the influence of streptozotocin-induced diabetes on the renal expression of bradykinin (BK) B₂ receptors (B₂KR), connective tissue growth factor (CTGF), transforming growth factor- (TGF-), and TGF- type II receptor (TGF-RII) and assessed the signaling mechanisms through which B₂KR activation may promote glomerular injury. Eight weeks after the induction of diabetes, renal mRNA levels of B₂KR, CTGF, and TGF- as well as protein levels of CTGF and TGF-RII were measured in control (C), diabetic (D), and insulin-treated diabetic (D+I) rats. Renal B₂KR and TGF- mRNA levels expressed relative to -actin mRNA levels and CTGF and TGF-RII protein levels were significantly increased in D and D+I rats compared with C rats (P < 0.03, n = 5). To assess the contribution of B₂KR activation on modulating the expression of CTGF, TGF-RII, and collagen I, mesangial cells (MC) were treated with BK (10^–8 M) for 24 h and CTGF and TGF-RII protein levels were measured by Western blots and collagen I mRNA levels were measured by RT-PCR. A two- to threefold increase in CTGF and TGF-RII protein levels was observed in response to BK stimulation (P < 0.001, n = 6). In addition, a marked increase in collagen I mRNA levels was observed in response to BK stimulation. Treatment of MC with BK (10^–8 M) for 5 min significantly increased the tyrosine phosphorylation of p60src kinase and of p42/p44 MAPK (P < 0.05, n = 4). Inhibition of src kinase by PP1 (10 µM) inhibited the increase in p42/p44 MAPK activation in response to BK. Finally, to determine whether BK stimulates CTGF, TGF-RII, and collagen I expression via activation of MAPK pathways, MC were pretreated with an inhibitor of p42/p44 MAPK (PD-98059) for 45 min, followed by BK (10^–8 M) stimulation for 24 h. Selective inhibition of p42/p44 MAPK significantly inhibited the BK-induced increase in CTGF, TGF-RII, and collagen I levels. These findings are the first to demonstrate that BK regulates the expression of CTGF, TGF-RII, and collagen I in MC and provide a mechanistic pathway through which B₂KR activation may contribute to the development of diabetic nephropathy.

glomerulosclerosis; diabetic nephropathy; connective tissue growth factor

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