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J Pharm Pharmacol. 2016 Feb;68(2):219-32. doi: 10.1111/jphp.12504. Epub 2016 Jan 28.

Ruboxistaurin attenuates diabetic nephropathy via modulation of TGF-β1/Smad and GRAP pathways.

Author information

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.

KEYWORDS:

GRAP; TGF-β1; diabetic nephropathy; ruboxistaurin; smad

PMID:
26817709
DOI:
10.1111/jphp.12504
[Indexed for MEDLINE]

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