title: AS101 prevents diabetic nephropathy progression and mesangial cell dysfunction: regulation of the AKT downstream pathway.
abstract: 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.
authors.affiliation: Safdié Institute for AIDS and Immunology Research, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Itay Israel
authors.initials: II
authors.lastname: Shemesh
authors.affiliation: Department of Nephrology and Hypertension, Rabin Medical Center, Petah-Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel.
authors.forename: Benaya
authors.initials: B
authors.lastname: Rozen-Zvi
authors.affiliation: Safdié Institute for AIDS and Immunology Research, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Yona
authors.initials: Y
authors.lastname: Kalechman
authors.affiliation: Department of Nephrology and Hypertension, Rabin Medical Center, Petah-Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel.
authors.forename: Uzi
authors.initials: U
authors.lastname: Gafter
authors.affiliation: Safdié Institute for AIDS and Immunology Research, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Sredni
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005030:Ethylenes / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects; D050527:Mesangial Cells / Q000187:drug effects / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000096:biosynthesis* / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D051900:Smad3 Protein / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D001786:Blood Glucose; D005030:Ethylenes; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C497787:Smad3 protein, rat; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; C487216:Pten protein, rat