Asma S Al-Onazi1, Nouf M Al-Rasheed1, Hala A Attia1,2, Nawal M Al-Rasheed1, Raeesa M Ahmed3, Maha A Al-Amin1, Coralie Poizat4. 1. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. 2. Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. 3. Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 4. Cardiovascular Research Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
Abstract
OBJECTIVE: To investigate whether ruboxistaurin (a selective PKC-β inhibitor) mediates renoprotective effect via interference with TGF-β1/Smad-GRAP cross-signalling. METHOD: Diabetes 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 FINDINGS: Data 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 showed a significant improvement in protein levels of TGF-β1 (P < 0.01), Smad2/3 (P < 0.01) and p-Smad3 (P < 0.001) in diabetic rats treated with ruboxistaurin compared to untreated. Importantly, the reduction in GRAP protein expression in diabetic kidney was prevented by treatment with ruboxistaurin. CONCLUSION: These data suggest that the renoprotective effect of ruboxistaurin is possibly due to down-regulation of TGF-β1/Smad pathway and normalization of GRAP protein expression.
OBJECTIVE: To investigate whether ruboxistaurin (a selective PKC-β inhibitor) mediates renoprotective effect via interference with TGF-β1/Smad-GRAP cross-signalling. METHOD:Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (55 mg/kg). Then, the diabeticrats 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 FINDINGS: Data showed that serum creatinine, kidney/body weight ratio and urinary albumin excretion significantly increased in diabeticrats. These changes were significantly attenuated by treatment with ruboxistaurin. A significant up-regulation of TGF-β1, Smad2 and Smad3 mRNA expression was observed in diabeticrats, which was alleviated by administration of ruboxistaurin. Furthermore, immunoblotting showed a significant improvement in protein levels of TGF-β1 (P < 0.01), Smad2/3 (P < 0.01) and p-Smad3 (P < 0.001) in diabeticrats treated with ruboxistaurin compared to untreated. Importantly, the reduction in GRAP protein expression in diabetic kidney was prevented by treatment with ruboxistaurin. CONCLUSION: These data suggest that the renoprotective effect of ruboxistaurin is possibly due to down-regulation of TGF-β1/Smad pathway and normalization of GRAP protein expression.
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