Failure to phosphorylate AKT in podocytes from mice with early diabetic nephropathy promotes cell death

Kidney Int. 2008 Jun;73(12):1385-93. doi: 10.1038/ki.2008.109. Epub 2008 Apr 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / enzymology
  • Albuminuria / pathology
  • Animals
  • Apoptosis
  • Cell Count
  • Diabetic Nephropathies / enzymology*
  • Diabetic Nephropathies / pathology*
  • Down-Regulation
  • Insulin / pharmacology
  • Kidney Glomerulus / enzymology
  • Kidney Glomerulus / pathology
  • Mice
  • Mice, Inbred Strains
  • Phosphorylation / drug effects
  • Podocytes / drug effects
  • Podocytes / enzymology*
  • Podocytes / pathology*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology


  • Insulin
  • Tumor Necrosis Factor-alpha
  • Proto-Oncogene Proteins c-akt