Abstract
Podocyte injury is closely related to proteinuria and the progression of chronic kidney disease (CKD). Currently, there is no conclusive understanding about the mechanisms involved in albumin overload and podocyte apoptosis response. In this study, we sought to explore the ways by which intracellular albumin can mediate podocyte apoptosis. Here, immortalized mouse podocytes were treated with bovine serum albumin (BSA) at different times and concentrations, in the presence or absence of SB203580 (0.1 µM, inhibitor of mitogen-activated-protein kinase – p38MAPK). Using immunofluorescence images, flow cytometry and immunoblotting, we observed a time-dependent intracellular accumulation of fluorescent albumin-FITC-BSA, followed by concentration-and time-dependent effect of intracellular albumin overload on podocyte apoptosis, which was mediated by increased expression of the chaperone glucose-regulated-protein 78 (GRP 78) and phosphorylated inositol-requiring enzyme 1 alpha (pIRE1-α), as well as protein kinase C delta (PKC-δ), p38MAPK and cleaved caspase 12 expression. SB203580 prevented the cleavage of caspase 12 and the albumin-mediated podocyte apoptosis. These results suggest that intracellular albumin overload is associated with endoplasmic reticulum (ER) stress and upregulation of PKC-δ/p38MAPK/caspase 12 pathway, which may be a target for future therapeutic of albumin-induced podocyte apoptosis.
Highlights
Podocytes are highly specialized renal epithelial cells in the Bowman’s space
Podocyte apoptosis was documented by flow cytometry
Albumin 5 mg/mL induced only early podocyte apoptosis, whereas albumin 10 mg/mL induced a significant increase in the early apoptosis but decreased the late apoptosis
Summary
Podocytes are highly specialized renal epithelial cells in the Bowman’s space. They regularly wrap around the glomerular basement membrane (GBM) of the glomerular capillaries and extend foot processes, which interdigitate with the same structures of the neighboring podocytes. In renal diseases, podocytes are injured and the complex architecture of the foot processes can be altered, leading to loss of the slit diaphragm or podocyte effacement. These processes result in proteinuria and progressive loss of kidney function[4,5]. Oxygen species (ROS) production are closely related to endoplasmic reticulum (ER) stress, PKC-δ13–15 and p38 MAPK activation, which together are associated with apoptotic responses[13,16,17,18] In view of these findings, we sought to explore the hypothesis that under intracellular albumin overload, the ER stress/PKC-δ/p38MAPK/caspase 12 signaling pathway can play a critical role in podocyte apoptosis. Our data advance the understanding of the cell signaling pathways responsible for albumin-induced podocyte apoptosis and may contribute to the development of preventive and therapeutic strategies for albuminuria-associated chronic kidney diseases (CKD)
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