Abstract
(Pro)renin receptor (PRR) expression is upregulated in diabetes. We hypothesized that PRR contributes to podocyte injury via activation of Wnt-β-catenin-snail signaling pathway. Mouse podocytes were cultured in normal (5 mM) or high (25 mM) D-glucose for 3 days. Compared to normal glucose, high glucose significantly decreased mRNA and protein expressions of podocin and nephrin, and increased mRNA and protein expressions of PRR, Wnt3a, β-catenin, and snail, respectively. Confocal microscopy studies showed significant reduction in expression and reorganization of podocyte cytoskeleton protein, F-actin, in response to high glucose. Transwell functional permeability studies demonstrated significant increase in albumin flux through podocytes monolayer with high glucose. Cells treated with high glucose and PRR siRNA demonstrated significantly attenuated mRNA and protein expressions of PRR, Wnt3a, β-catenin, and snail; enhanced expressions of podocin mRNA and protein, improved expression and reorganization of F-actin, and reduced transwell albumin flux. We conclude that high glucose induces podocyte injury via PRR-Wnt- β-catenin- snail signaling pathway.
Highlights
High glucose contributes to glomerular injury and a progressive renal function loss, leading to end-stage renal disease (ESRD)[1,2]
PRR mRNA and protein expression Compared to normal glucose, high glucose significantly increased expression of PRR mRNA by 285% (Fig 1A, p,0.001) and protein by 57% (Fig 1B, p,0.05)
We investigated the role of PRR in high glucose induced podocytes structure and function changes, and explored the mechanisms mediating this pathological process
Summary
High glucose contributes to glomerular injury and a progressive renal function loss, leading to end-stage renal disease (ESRD)[1,2]. Podocytes are important component of the glomerular basement membrane and involved in several key functions, mainly limiting albumin filtration [3]. Previous studies identified podocyte injury as a key early event leading to glomerular disease [6], seen in patients with diabetic nephropathy [7,8]. The mechanisms involved in high glucose induced podocyte injury are not well established. Hyperglycemia activates all components of the renin-angiotensin system (RAS) [9,10], contributing to the development of diabetic nephropathy. Despite the utilization of RAS inhibitors, some patients with this disease continue to progress to ESRD [11,12]
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