title: Failure to phosphorylate AKT in podocytes from mice with early diabetic nephropathy promotes cell death.
abstract: Loss of podocytes by apoptosis characterizes the early stages of diabetic nephropathy. To examine its mechanism we studied glomeruli and podocytes isolated from db/db mice with early diabetic nephropathy and albuminuria. Phosphorylation of AKT (protein kinase B, a key survival protein) was found to be lower in the glomeruli of 12 week old db/db compared to db/+ mice. In vitro, insulin phosphorylated AKT solely in podocytes from db/+ mice. Serum deprivation and exposure to tumor necrosis factor-alpha significantly compromised cell viability in podocytes from db/db but not from db/+ mice, and this was associated with a significant decrease in AKT phosphorylation. Inhibition of AKT was necessary to achieve the same degree of cell death in db/+ podocytes. Our study shows that podocyte inability to respond to insulin and susceptibility to cell death may partially account for the decreased podocyte number seen in early diabetic nephropathy.
authors.affiliation: Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tejada
authors.forename: P
authors.initials: P
authors.lastname: Catanuto
authors.forename: A
authors.initials: A
authors.lastname: Ijaz
authors.forename: J V
authors.initials: JV
authors.lastname: Santos
authors.forename: X
authors.initials: X
authors.lastname: Xia
authors.forename: P
authors.initials: P
authors.lastname: Sanchez
authors.forename: N
authors.initials: N
authors.lastname: Sanabria
authors.forename: O
authors.initials: O
authors.lastname: Lenz
authors.forename: S J
authors.initials: SJ
authors.lastname: Elliot
authors.forename: A
authors.initials: A
authors.lastname: Fornoni
mesh_terms: D000419:Albuminuria / Q000201:enzymology / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000473:pathology*; D015536:Down-Regulation; D007328:Insulin / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D010766:Phosphorylation / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt