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Abstract
Apoptosis of podocytes contributes to proteinuria in many chronic kidney diseases. The cytokine, tumor necrosis factor-α (TNF-α) is thought to be involved in podocyte apoptosis, but the underlying mechanism is not understood. In our study, we established a model of TNF-α-induced apoptosis by isolating primary podocytes from mice. After exposing cells to TNF-α, we determined the expression levels of heterogeneous nuclear ribonucleoprotein K (hnRNP K) and cellular FLICE-inhibitory protein (c-FLIP) and the phosphorylation levels of glycogen synthase kinase β (GSK3β) and extracellular signal-regulated kinase (ERK). We then knocked down or overexpressed the levels of hnRNP K and observed its effects on the expressions of c-FLIP, caspase-8, caspase-3, and the phosphorylation of GSK3β and ERK. In addition, we examined the percentage of cells undergoing apoptosis and studied cell cycle distribution. We found that TNF-α induced apoptosis in podocytes and that the expressions of hnRNP K and c-FLIP were significantly decreased, whereas the phosphorylations of GSK3β and ERK were significantly increased. Both gene knockdown and overexpression of hnRPN K resulted in varied expressions/phosphorylations of c-FLIP, GSK3β, and ERK. Moreover, decreased hnRPN K expression contributed to increased levels of caspase-8 and capase-3, as well as an increase in cell apoptosis and G0/G1 arrest. In conclusion, down-regulated expression of hnRNP K by TNF-α resulted in a decrease in the expression of c-FLIP as well as increases in phosphorylated GSK3β, ERK, caspase-8, and caspase-3, and then critically contributed to the podocyte apoptosis.
Highlights
As a highly differentiated and structurally complex organ, the kidney is composed of approximately a million clusters of looping blood vessels called glomeruli
The markers associated with apoptosis, caspase-3, and caspase-8, exhibited a significant increase in response to heterogeneous nuclear ribonucleoprotein K (hnRNP K) knockdown. These results suggest that tumor necrosis factor-α (TNF-α) induces podocyte apoptosis by decreasing heterogeneous ribonucleoproteins (hnRNPs) K expression, and decreasing levels of cellular FLICE-inhibitory protein (c-FLIP), and increasing levels of glycogen synthase kinase β (GSK3β) and extracellular signal-regulated kinase (ERK) phosphorylation
Increased proteinuria is an indication of a decline in renal function, regardless of baseline estimated glomerular filtration rate [17]
Summary
As a highly differentiated and structurally complex organ, the kidney is composed of approximately a million clusters of looping blood vessels called glomeruli. The outer part of the glomerular basement membrane is covered with extremely ramified cells called podocytes. As blood flows through each glomerulus, water and metabolic wastes are filtered through capillary walls by the surrounding podocytes. Podocytes function as the final barrier to protein loss and are crucial in maintaining the integrity of the glomerular filtration barrier [1]. Apoptosis is a major reason for podocyte loss and sequentially results in glomerular diseases [2]. Recent studies revealed that podocyte apoptosis and loss are observed in many forms of human and experimental glomerular diseases, including minimal change disease (MCD), focal segmental glomerulosclerosis, membranous glomerulopathy, diabetes mellitus, and lupus nephritis [1]. Preventing podocyte apoptosis is an attractive therapy for treating these kidney diseases. The underlying mechanisms involved in podocyte apoptosis are still not fully understood
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