AS101 prevents diabetic nephropathy progression and mesangial cell dysfunction: regulation of the AKT downstream pathway

Diabetic nephropathy (DN) is characterized by proliferation of mesangial cells, mesangial expansion, hypertrophy and extracellular matrix accumulation. Previous data have cross-linked PKB (AKT) to TGFβ induced matrix modulation. The non-toxic compound AS101 has been previously shown to favorably aff...

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Bibliographic Details
Published in:PloS one 2014-12, Vol.9 (12), p.e114287
Main Authors: Shemesh, Itay Israel, Rozen-Zvi, Benaya, Kalechman, Yona, Gafter, Uzi, Sredni, Benjamin
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Accumulation
AKT protein
Analysis
Animal models
Animals
Biocompatibility
Biology and life sciences
Blood Glucose
Cell cycle
Cell growth
Cell proliferation
Collagen
Crosslinking
Development and progression
Diabetes
Diabetes mellitus
Diabetes Mellitus, Experimental - drug therapy
Diabetes Mellitus, Experimental - genetics
Diabetes Mellitus, Experimental - pathology
Diabetic nephropathies
Diabetic Nephropathies - drug therapy
Diabetic Nephropathies - genetics
Diabetic Nephropathies - pathology
Diabetic nephropathy
Ethylenes - administration & dosage
Extracellular matrix
FOXO3 protein
Gene Expression - drug effects
Glucose
Hyperglycemia
Hypertension
Hypertrophy
Immunology
Inhibition
Kidney diseases
Kidneys
Kinases
Leukemia
Life sciences
Medicine and Health Sciences
Mesangial cells
Mesangial Cells - drug effects
Mesangial Cells - pathology
Nephrology
Nephropathy
Oncogene Protein v-akt - biosynthesis
Oncogene Protein v-akt - genetics
Pharmacology
Phosphatidylinositol 3-Kinases - biosynthesis
Phosphatidylinositol 3-Kinases - genetics
Phosphorylation
Prevention
Proteins
Proteinuria
PTEN Phosphohydrolase - biosynthesis
PTEN protein
Rats
Rodents
Signal transduction
Signal Transduction - drug effects
Smad3 protein
Smad3 Protein - biosynthesis
Smad3 Protein - genetics
Streptozocin
TOR protein
Transforming Growth Factor beta - biosynthesis
Transforming growth factors
Urine
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Summary:Diabetic nephropathy (DN) is characterized by proliferation of mesangial cells, mesangial expansion, hypertrophy and extracellular matrix accumulation. Previous data have cross-linked PKB (AKT) to TGFβ induced matrix modulation. The non-toxic compound AS101 has been previously shown to favorably affect renal pathology in various animal models and inhibits AKT activity in leukemic cells. Here, we studied the pharmacological properties of AS101 against the progression of rat DN and high glucose-induced mesangial dysfunction. In-vivo administration of AS101 to Streptozotocin injected rats didn't decreased blood glucose levels but ameliorated kidney hypotrophy, proteinuria and albuminuria and downregulated cortical kidney phosphorylation of AKT, GSK3β and SMAD3. AS101 treatment of primary rat glomerular mesangial cells treated with high glucose significantly reduced their elevated proliferative ability, as assessed by XTT assay and cell cycle analysis. This reduction was associated with decreased levels of p-AKT, increased levels of PTEN and decreased p-GSK3β and p-FoxO3a expression. Pharmacological inhibition of PI3K, mTORC1 and SMAD3 decreased HG-induced collagen accumulation, while inhibition of GSK3β did not affect its elevated levels. AS101 also prevented HG-induced cell growth correlated to mTOR and (rp)S6 de-phosphorylation. Thus, pharmacological inhibition of the AKT downstream pathway by AS101 has clinical potential in alleviating the progression of diabetic nephropathy.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0114287