ANG II is a critical mediator of
diabetic nephropathy. Pharmacologic inhibition of ANG II slows
disease progression beyond what could be predicted by the blood pressure lowering effects alone, suggesting the importance of nonhemodynamic pathways of ANG II in mediating disease. Podocyte injury and loss are cardinal features of
diabetic nephropathy. Mounting evidence suggests that the podocyte is a direct target of ANG II-mediated signaling in diabetic renal disease. We have tested the hypothesis that high
glucose leads to the activation of a local
angiotensin system in podocytes and delineated the underlying pathways involved. Cultured podocytes were exposed to standard
glucose (5 mM), high
glucose (40 mM), or
mannitol as an osmotic control. ANG II levels in cell lysates were measured in the presence or absence of inhibitors of
angiotensin-converting enzyme (
captopril),
chymase (
chymostatin), and
renin (
aliskiren) activity. The effects of
glucose on
renin and
angiotensin subtype 1 receptor expression and
protein levels were determined. Exposure to high
glucose resulted in a 2.1-fold increase ANG II levels mediated through increased
renin activity, as exposure to high
glucose increased
renin levels and preincubation with
Aliskiren abrogated
glucose-induced ANG II production. Relevance to the in vivo setting was demonstrated by showing glomerular upregulation of the
prorenin receptor in a podocyte distribution early in the course of experimental
diabetic nephropathy. Furthermore, high
glucose increased
angiotensin subtype 1 receptor levels by immunofluorescence and Western blot. Taken together, the resultant activation of a local renin angiotensin system by high
glucose may promote progressive podocyte injury and loss in
diabetic nephropathy.