AS101 Prevents Diabetic Nephropathy Progression and Mesangial Cell Dysfunction: Regulation of the AKT Downstream Pathway

作者：Shemesh Itay Israel^*; Rozen Zvi Benaya; Kalechman Yona; Gafter Uzi; Sredni Benjamin

来源：PLos One, 2014, 9(12): e114287.

DOI：10.1371/journal.pone.0114287

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 TGF beta induced matrix modulation. The nontoxic compound AS101 has been previously shown to favorably affect renal pathology in various animal models and inhibits AKTactivity 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%26apos;t decreased blood glucose levels but ameliorated kidney hypotrophy, proteinuria and albuminuria and downregulated cortical kidney phosphorylation of AKT, GSK3 beta 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-GSK3 beta and p-FoxO3a expression. Pharmacological inhibition of PI3K, mTORC1 and SMAD3 decreased HG-induced collagen accumulation, while inhibition of GSK3 beta did not affect its elevated levels. AS101 also prevented HG-induced cell growth correlated to mTOR and (rp) S6 dephosphorylation. Thus, pharmacological inhibition of the AKT downstream pathway by AS101 has clinical potential in alleviating the progression of diabetic nephropathy.

• 出版日期2014-12-4