Abstract
BackgroundMicroalbuminuria is an early lesion during the development of diabetic nephropathy. The loss of high molecular weight proteins in the urine is usually associated with decreased expression of slit diaphragm proteins. Nephrin, is the major component of the glomerular slit diaphragm and loss of nephrin has been well described in rodent models of experimental diabetes as well as in human diabetic nephropathy.Methodology/Principal FindingsIn this manuscript we analyzed the role of PKC-alpha (PKCα) on endocytosis of nephrin in podocytes. We found that treatment of diabetic mice with a PKCα-inhibitor (GÖ6976) leads to preserved nephrin expression and reduced proteinuria. In vitro, we found that high glucose stimulation would induce PKCα protein expression in murine and human podocytes. We can demonstrate that PKCα mediates nephrin endocytosis in podocytes and that overexpression of PKCα leads to an augmented endocytosis response. After PKC-activation, we demonstrate an inducible association of PKCα, PICK1 and nephrin in podocytes. Moreover, we can demonstrate a strong induction of PKCα in podocytes of patients with diabetic nephropathy.Conclusions/SignificanceWe therefore conclude that activation of PKCα is a pathomechanistic key event during the development of diabetic nephropathy. PKCα is involved in reduction of nephrin surface expression and therefore PKCα inhibition might be a novel target molecule for anti-proteinuric therapy.
Highlights
The activation of protein kinase C (PKC) in the kidney is a well known pathway of the diabetic milieu
PKCa is upregulated in podocytes in experimental as well as in human diabetic nephropathy First, we wanted to examine whether diabetes leads to changes in PKCa expression in mice and in patients with diabetic nephropathy
PKCa regulates nephrin endocytosis via PICK1 To understand the observation of reduced proteinuria and preserved nephrin expression mechanistically, we investigated whether PKCa interacts with nephrin and whether that interaction would lead to nephrin internalization
Summary
The activation of protein kinase C (PKC) in the kidney is a well known pathway of the diabetic milieu. We previously described that PKCa deficient mice show a better outcome after streptozotocin (STZ) induced diabetes with less proteinuria and preserved nephrin expression [5,6]. To study the involvement of PKCa in proteinuria development in diabetic nephropathy, we treated mice after streptozotocin induced diabetes with a synthetic PKCa inhibitor (GO 6976), which could prevent proteinuria development and led to preserved nephrin expression. Biochemical analysis in wildtype and PKCa deficient podocyte lines revealed a central role for PKCa in endocytosis of the slit diaphragm component nephrin. This endocytosis mediation could account for the preserved nephrin expression in vivo. Nephrin, is the major component of the glomerular slit diaphragm and loss of nephrin has been well described in rodent models of experimental diabetes as well as in human diabetic nephropathy
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