Effect of Ruboxistaurin on Urinary Transforming Growth Factor- in Patients With Diabetic Nephropathy and Type 2 Diabetes (original) (raw)
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Ruboxistaurin attenuates diabetic nephropathy via modulation of TGF-β1/Smad and GRAP pathways
Journal of Pharmacy and Pharmacology, 2016
ObjectiveTo investigate whether ruboxistaurin (a selective PKC-β inhibitor) mediates renoprotective effect via interference with TGF-β1/Smad-GRAP cross-signalling.MethodDiabetes was induced in rats by a single intraperitoneal injection of streptozotocin (55 mg/kg). Then, the diabetic rats were treated with ruboxistaurin (10 mg/kg, p.o) for 6 weeks. Valsartan (15 mg/kg, p.o) was used as a positive control. After 6 weeks of treatment, diabetic nephropathy biomarkers were assessed. TGF-β1, Smad2, and Smad3 mRNA and protein levels were detected using qPCR and western blot analysis.Key findingsData showed that serum creatinine, kidney/body weight ratio and urinary albumin excretion significantly increased in diabetic rats. These changes were significantly attenuated by treatment with ruboxistaurin. A significant up-regulation of TGF-β1, Smad2 and Smad3 mRNA expression was observed in diabetic rats, which was alleviated by administration of ruboxistaurin. Furthermore, immunoblotting showe...
Diabetes Research and Clinical Practice, 2006
With the aim to determine the influence of reducing systolic blood pressure in urinary TGF-b1 of type 2 diabetes (DM2) with diabetic nephropathy (DN), 21 subjects with type 2 diabetes and proteinuria >500 mg/24 h were studied. Amlodipine and ramipril were added to their previous antihypertensive treatment for 12 weeks. Urinary TGF-b1 (UTGF-b1) was determined at 0, 4, 8 and 12 weeks. Plasma TGF-b1 was determined at 0 and 12 weeks. Subjects whose mean systolic blood pressure (SBP) during treatment were under 140 mmHg were grouped as the better SBP controlled group (n = 11) and those with SBP equal to or greater than 140 mHg were grouped in a moderate SBP controlled group (n = 10). Compared to baseline, mean log UTGF-b1 at 4, 8 and 12 weeks decreased (À0.22 AE 0.15 pg/mg; p = 0.04) in better SBP controlled group but not in the moderate SBP controlled group (À0.12 AE 0.08 pg/mg, p = 0.82). Mean SBP correlated with UTGF-b1 (r = 0.458, p = 0.0357), and this effect was independent of HbA1c ( p = 0.042). By controlling SBP in DM2 subjects with DN we might decrease UTGF-b1. We propose that reduction of UTGF-b1 is due to a decrease in renal TGF-b1 production. #
Kidney Outcomes in Long-Term Studies of Ruboxistaurin for Diabetic Eye Disease
Clinical Journal of the American Society of Nephrology, 2007
Background: A pilot study showed that ruboxistaurin (RBX), a protein kinase C  inhibitor, significantly decreased albuminuria and stabilized kidney function over 1 yr in patients who had diabetic nephropathy and persistent macroalbuminuria despite receiving the current standard of care, including renin-angiotensin system inhibition. In contrast, in a trial of patients with diabetic retinopathy, investigators reported the adverse event "diabetic nephropathy" more frequently in patients who received RBX. Design, setting, participants, and measurements: The purpose of this study was to evaluate long-term effects of RBX on kidney outcomes among patients with diabetic eye disease in three diabetic retinopathy trials (n ؍ 1157). Baseline-to-study end changes in estimated GFR (eGFR) were calculated. Kidney outcomes included doubling of serum creatinine, development of advanced chronic kidney disease (stages 4 to 5), and death. Results: Baseline eGFR was 81.6 ؎ 26.0 ml/min per 1.73 m 2. In the combined placebo and RBX treatment groups, eGFR decreased by 11.0 ؎ 19.6 ml/min per 1.73 m 2 during median follow-up of 33 to 39 mo. At least one kidney outcome occurred in 11.3% of patients. Frequency of doubling of serum creatinine was 6.0%, progression to advanced chronic kidney disease was 4.1%, and death was 4.1%. Kidney outcome rates did not differ by treatment assignment. Conclusions: Long-term kidney outcomes in patients with diabetic eye disease were similar in placebo and RBX groups. In conclusion, large-scale, prospective trials in patients with diabetic nephropathy are needed to confirm safety and potential benefits of RBX on clinical outcomes.
Diabetes research and clinical practice, 2006
With the aim to determine the influence of reducing systolic blood pressure in urinary TGF-beta1 of type 2 diabetes (DM2) with diabetic nephropathy (DN), 21 subjects with type 2 diabetes and proteinuria >500 mg/24 h were studied. Amlodipine and ramipril were added to their previous antihypertensive treatment for 12 weeks. Urinary TGF-beta1 (UTGF-beta1) was determined at 0, 4, 8 and 12 weeks. Plasma TGF-beta1 was determined at 0 and 12 weeks. Subjects whose mean systolic blood pressure (SBP) during treatment were under 140 mmHg were grouped as the better SBP controlled group (n = 11) and those with SBP equal to or greater than 140 mHg were grouped in a moderate SBP controlled group (n = 10). Compared to baseline, mean log UTGF-beta1 at 4, 8 and 12 weeks decreased (-0.22 +/- 0.15 pg/mg; p = 0.04) in better SBP controlled group but not in the moderate SBP controlled group (-0.12 +/- 0.08 pg/mg, p = 0.82). Mean SBP correlated with UTGF-beta1 (r = 0.458, p = 0.0357), and this effect w...
Urinary TGF-β1 was not independently associated with renal function in diabetes mellitus
2018
Background Several clinical studies have shown increased level of urinary TGF-β1 in diabetic nephropathy patients and its correlation with urine albumin-to-creatinine ratio (UACR), but other studies showed different results. Because of this contradiction, this study aims to analyze the correlation between urinary TGF-β1 concentration and UACR, and also estimated glomerular filtration rate (eGFR) in type 2 diabetes mellitus (DM) patients by controlling some confounding factors. Methods This was a cross-sectional study, and the samples were obtained using consecutive sampling technique. The study was performed on 99 subjects (62 DM normoalbuminuria patients, 27 DM albuminuria patients, and 10 non-DM patients as controls) at Pasar Minggu Community Health Center. Urinary TGF-β1 concentration was measured by ELISA, and UACR was measured using immunoturbidimetry and an enzymatic colorimetric method. The eGFR value was calculated based on serum creatinine using Chronic Kidney Disease Epide...
American Journal of Hypertension, 2012
nature publishing group brief communications Renin inhibitors strongly increase the concentration of renin and prorenin due to an attenuation of the negative feedback of angiotensin II on the renin release. 1 This could potentially be harmful because high levels of renin and prorenin may stimulate the (pro)renin receptor, thus inducing profibrotic effects. 2 Gross and colleagues demonstrated the antifibrotic nephroprotective effects of the direct renin inhibitor, aliskiren, on progressive renal fibrosis in a nonhypertensive mouse model. 3 Compared with placebo-treated controls, the accumulation of the extracellular matrix, renal scarring and the levels of transforming growth factor-β1 (TGF-β1), and connective tissue growth factor were decreased in the treated mice. Previously, a reduction in the magnitude of glomerulosclerosis and intersti tial fibrosis has been demonstrated in diabetic animals treated with aliskiren. 4 Other studies have shown that the addition of aliskiren to the angiotensin II receptor blocker (ARB), valsartan exerts a synergistic protection against renal fibrosis through the attenuation of the messenger RNA expression TGF-β1, infiltration of monocytes/macrophages, and interstitial collagen deposition. 5 In this paper, we present the results of our recent clinical study performed in this field. Methods conclusions The study shows that both aliskiren and perindopril suppress TGF-β1 in patients with chronic kidney diseases. This effect was observed despite significant increases in the renin and prorenin concentrations. Further studies involving histological assessments are required to elucidate the exact impact of these agents on renal fibrosis.
Kidney International, 2005
Background. Connective tissue growth factor (CTGF) is an important profibrotic cytokine implicated in development of diabetic glomerulosclerosis. Urinary CTGF is reported to be significantly increased in patients with diabetic nephropathy. The present study aimed to investigate the short-and long term effects of angiotensin II receptor blockade by Losartan on urinary CTGF levels in hypertensive type 1 diabetic patients with diabetic nephropathy.