Glucose-Induced Reactive Oxygen Species Cause Apoptosis of Podocytes and
Podocyte Depletion at the Onset of Diabetic Nephropathy
Authors Katalin Susztak, Amanda C. Raff, Mario Schiffer, Erwin P. Böttinger
Submitted By Erwin Bottinger on 9/25/2005
Status Published
Journal Diabetes
Year 2006
Date Published 1/1/2006
Volume : Pages 55 : 225 - 233
PubMed Reference 16380497
Abstract Diabetic Nephropathy is the most common cause of end stage renal disease in the
US. Recent studies demonstrate that loss of podocytes is an early feature of DNP
that predicts its progressive course. Cause and consequences of podocyte loss
during early DNP remain poorly understood. Here we demonstrate that podocyte
apoptosis increased sharply with onset of hyperglycemia in Ins2Akita (Akita)
mice with T1DM and Leprdb/db (db/db) mice with obesity and T2DM. Podocyte
apoptosis coincided with the onset of urinary albumin excretion (UAE) and
preceded significant losses of podocytes in Akita (37% reduction) and db/db (27%
reduction) mice. Increased extracellular glucose (30 mM) rapidly stimulated
generation of intracellular reactive oxygen species (ROS) through NADPH oxidase
and mitochondrial pathways, lead to activation of proapoptotic p38
mitogen-activated protein kinase (MAPK), caspase 3 and apoptosis of
conditionally-immortalized podocytes in vitro. Chronic inhibition of NADPH
oxidase prevented podocyte apoptosis and ameliorated podocyte depletion, UAE,
and mesangial matrix expansion in db/db mice. In conclusion, our results
demonstrate for the first time
that glucose-induced ROS production initiates podocyte apoptosis and podocyte
depletion in vitro and in vivo and suggest that podocyte apoptosis/depletion
represent novel early pathomechanism(s) leading to DNP in murine T1DM and T2DM


Ins2insulin II