Connective tissue growth factor (CTGF) is one of the candidate factors mediating downstream events of transforming growth factor-β (TGF-β), but its role in fibrogenic properties of TGF-β and in tubulointerstitial fibrosis has not yet been clarified. Using unilateral ureteral obstruction (UUO) in rats, we analyzed gene expression of TGF-β1, CTGF, and fibronectin. We further investigated the effect of blockade of endogenous CTGF on TGF-β-induced fibronectin expression in cultured rat renal fibroblasts by antisense oligodeoxynucleotide (ODN) treatment. After UUO, CTGF mRNA expression in the obstructed kidney was significantly upregulated subsequent to TGF-β1, followed by marked induction of fibronectin mRNA. By in situ hybridization, CTGF mRNA was detected mainly in the interstitial fibrotic areas and tubular epithelial cells as well as in parietal glomerular epithelial cells in the obstructed kidney. The interstitial cells expressing CTGF mRNA were also positive for α-smooth muscle actin. CTGF antisense ODN transfected into cultured renal fibroblasts significantly attenuated TGF-β-stimulated upregulation of fibronectin mRNA and protein compared with control ODN transfection, together with inhibited synthesis of type I collagen. With the use of a reporter assay, rat fibronectin promoter activity was increased by 2.5-fold with stimulation by TGF-β1, and this increase was abolished with antisense CTGF treatment. Thus CTGF plays a crucial role in fibronectin synthesis induced by TGF-β, suggesting that CTGF blockade could be a possible therapeutic target against tubulointerstitial fibrosis.

Aim:The effects of exercise intervention and to assess its long-term efficacy in preventing subsequent cardiovascular events in patients with type 2 diabetes were little known on randomized controlled trial. Methods: Thirty-eight type 2 diabetic patients (21 men and 17 women) were assigned to either the exercise group (n 21) or the control group without exercise training (n 17) by simple randomization. The exercise training group was scheduled for aerobic and resistance exercise programs for 3 months. After the 3-month, we investigated endothelial function, insulin resistance, adipocytokines and inflammatory markers. The endothelial function was evaluated by examining a flow-mediated endothelium-dependent vasodilatation (FMD). Furthermore, we followed the incidence of cardiovascular events for 24 months. Results: After 3-month, HbA1C was decreased significantly in both groups. FMD was increased from 7.3 4.7% to 10.9 6.2% only in the exercise group ( p 0.05). Long-term follow-up data showed that the control group developed cardiovascular events more frequently than did the exercise group ( p 0.05). Conclusions: Exercise improves endothelial dysfunction independently of glycemic control and insulin sensitivity in patients with type 2 diabetes. The beneficial effects of 3-month exercise to reduce cardiovascular events persist for 24 months. J Atheroscler Thromb, 2010; 17:828-833.

No abstract

Abstract. Local production of prostaglandins (PGs) in the kidney is increased in clinical and experimental diabetic nephropathy, but the role of PGs in the pathogenesis and progression of diabetic nephropathy has remained unclear. It is here shown that an orally active antagonist selective for the PGE receptor EP1 subtype potently prevents the progression of nephropathy in streptozotocin-induced diabetic rats. The effects are shown by ameliorated renal and glomerular hypertrophy, decreased mesangial expansion, inhibited transcriptional activation of transforming growth factor-␤ (TGF-␤) and fibronectin, and complete suppression of proteinuria. In vitro, this agent completely inhibits TGF-␤ and fibronectin upregulation in mesangial cells cultured under high-glucose conditions. These data indicate that the PGE2-EP1 system plays a crucial role in the development of diabetic renal injury in rats. It is further shown that both the EP1 antagonist and aspirin, a nonselective PG synthase inhibitor, markedly attenuate mesangial expansion, whereas only the EP1 antagonist inhibits glomerular hypertrophy and proteinuria, which suggests that these changes are caused by different mechanisms. This study reveals a potential usefulness of selective EP1 blockade as a novel therapeutic strategy for diabetic nephropathy and also brings a new insight into our understanding of this disease.

Background and Purpose-Chronic kidney disease (CKD) is increasingly recognized as an independent risk factor for stroke and myocardial infarction (MI). Few studies, however, have examined the relationship between blood pressure (BP) category and these diseases in subjects with and without CKD. Methods-We studied 5494 Japanese individuals (ages 30 to 79, without stroke or MI at baseline) who completed a baseline survey and received follow-up through December 2005. The glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease study equation modified by the Japanese coefficient. CKD was defined as an estimated GFR Ͻ60 mL/min/1.73m