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

Asma S. Al-Onazi, Nouf M. Al-Rasheed, Hala A. Attia, Nawal M. Al-Rasheed, Raeesa M. Ahmed, Maha A. Al-Amin, Coralie Poizat

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8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)219-232
Number of pages14
JournalJournal of Pharmacy and Pharmacology
Volume68
Issue number2
DOIs
Publication statusPublished - 1 Feb 2016

Fingerprint

ruboxistaurin
Diabetic Nephropathies
Valsartan
Smad3 Protein
Kidney
Messenger RNA
Proteins
Streptozocin
Intraperitoneal Injections
Immunoblotting
Albumins
Creatinine
Up-Regulation
Therapeutics
Down-Regulation
Biomarkers
Western Blotting
Body Weight

Keywords

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

Cite this

Al-Onazi, Asma S. ; Al-Rasheed, Nouf M. ; Attia, Hala A. ; Al-Rasheed, Nawal M. ; Ahmed, Raeesa M. ; Al-Amin, Maha A. ; Poizat, Coralie. / Ruboxistaurin attenuates diabetic nephropathy via modulation of TGF-β1/Smad and GRAP pathways. In: Journal of Pharmacy and Pharmacology. 2016 ; Vol. 68, No. 2. pp. 219-232.
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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.",
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Ruboxistaurin attenuates diabetic nephropathy via modulation of TGF-β1/Smad and GRAP pathways. / Al-Onazi, Asma S.; Al-Rasheed, Nouf M.; Attia, Hala A.; Al-Rasheed, Nawal M.; Ahmed, Raeesa M.; Al-Amin, Maha A.; Poizat, Coralie.

In: Journal of Pharmacy and Pharmacology, Vol. 68, No. 2, 01.02.2016, p. 219-232.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Ruboxistaurin attenuates diabetic nephropathy via modulation of TGF-β1/Smad and GRAP pathways

AU - Al-Onazi, Asma S.

AU - Al-Rasheed, Nouf M.

AU - Attia, Hala A.

AU - Al-Rasheed, Nawal M.

AU - Ahmed, Raeesa M.

AU - Al-Amin, Maha A.

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N2 - 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.

AB - 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.

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KW - GRAP

KW - ruboxistaurin

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KW - TGF-β1

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