Background@#
Ceramides are associated with metabolic
complications including
diabetic nephropathy in
patients with diabetes.Recent studies have reported that
podocytes play a pivotal
role in the progression of
diabetic nephropathy. Also,
mitochondrial dysfunction is known to be an early event in
podocyte injury. Thus, we tested the hypothesis that
ceramide accumulation in
podocytes induces mitochondrial damage through
reactive oxygen species (ROS)
production in
patients with
diabetic nephropathy. @*
Methods@#We used Otsuka Long Evans Tokushima Fatty (OLETF)
rats and
high-fat diet (HFD)-fed
mice. We fed the
animals either a control- or a myriocin-containing
diet to evaluate the effects of the
ceramide. Also, we assessed the effects of
ceramide on intracellular ROS generation and on
podocyte autophagy in cultured
podocytes. @*Results@#
OLETF rats and HFD-fed
mice showed
albuminuria, histologic features of
diabetic nephropathy, and
podocyte injury, whereas myriocin
treatment effectively treated these
abnormalities. Cultured
podocytes exposed to agents predicted to be
risk factors (high
glucose, high
free fatty acid, and
angiotensin II in combination [GFA]) showed an increase in
ceramide accumulation and ROS generation in
podocyte mitochondria. Pretreatment with myriocin reversed GFA-induced mitochondrial ROS generation and prevented
cell death. Myriocin-pretreated
cells were protected from GFA-induced disruption of mitochondrial integrity. @*Conclusion@#We showed that mitochondrial
ceramide accumulation may result in
podocyte damage through ROS
production.Therefore, this signaling pathway could become a pharmacological target to
abate the development of
diabetic kidney disease.