AF1q Contributes to Adriamycin-Induced Podocyte Injury by Activating Wnt/β-Catenin Signaling

Abstract

Background/Aims: Injury of podocytes plays an important role in decline of glomerular filtration and proteinuria. It is well-known that proteinuria is associated with numerous chronic kidney diseases (CKD). However, the underlying mechanism of podocyte injury remains unclear. Methods: We used reverse transcription-quantitative PCR (RT-qPCR) to compare the expression level of the ALL1-fused from the chromosome 1q (AF1q) gene in mice and mouse podocytes (MPC5) with or without Adriamycin (ADR) treatment. The effects of AF1q on Wnt/ β-catenin signaling were investigated by determining the expressions of desmin, snail, WT1, nephrin and E-cadherin using western blotting. Results: We found that AF1q expression was elevated in podocytes treated with ADR than untreated cells. AF1q overexpression directly led to podocytes injury with increased levels of desmin and snail. Luciferase activity of TOPflash reporter was significantly increased in cells with AF1q overexpression than wild type cells whereas deletion of T-cell-factor-7 (TCF7) eliminated this effect. Immunoprecipitation assay evidenced that AF1q interacted with TCF7 and promoted both transcriptional and translational expressions of TCF7. Overexpression of AF1q increased protein expression of β-catenin. However, in podocytes with deletion of TCF7, AF1q was not able to promote β-catenin expression. Conclusion: Our findings demonstrated that aberrant expression of AF1q may activate Wnt/β-catenin signaling and result in podocyte injury.

Palmitic Acid-Induced Podocyte Apoptosis via the Reactive Oxygen Species-Dependent Mitochondrial Pathway

“…Podocytes play a key role in glomerular selective filtration function [10, 11]. Podocyte dysfunction or injury induced by various stresses and pathological stimuli is thought to be critical for the pathogenesis of proteinuria and glomerular diseases [12, 13].…”

STAT1-p53-p21axis-dependent stress-induced progression of chronic nephrosis in adriamycin-induced mouse model

“…ADR-induced nephrotic mouse model characterized by podocyte injury, glomerulosclerosis and tubulointerstitial inflammation (13). However, due to high accumulation in the kidney, it causes severe nephrotoxicity, such as elevated serum creatinine and proteinuria levels (13,14). In the present study, we continued to investigate STAT1-p53-p21axis involved in the development of adriamycin (ADR)-induced CN in a classical mouse model.…”

Mesenchymal Stem Cells Ameliorate Renal Inflammation in Adriamycin-induced Nephropathy

“…ADR shows the toxicity to podocytes, which might be resulted in the renal inflammation (134). Podocytes are highly specialized cells maintaining the glomerular filtration barrier, and podocyte injury is observed in various renal diseases (3334).…”

“…Podocytes are highly specialized cells maintaining the glomerular filtration barrier, and podocyte injury is observed in various renal diseases (3334). Several studies showed that MSCs inhibited podocyte apoptosis via epithelial growth factor, VEGF, CCAAT/enhancer binding protein-α, and β-catenin in ADR-induced and a diabetic nephropathy (3434). Consistently, our data demonstrate that MSCs significantly decrease the expression of the podocyte injury marker desmin in the kidney of ADR-treated mice and significantly inhibit pro-apoptotic BAX expression in ADR-treated podocytes in an in vitro co-culture setting.…”

“…ADR is an anti-neoplastic anthracycline isolated from Streptomyces peucetius and has been widely used for the treatment of patients with different cancers; however, it causes severe nephrotoxicity because of the high accumulation in the kidney (2). ADR is toxic to endothelial cells and podocytes, resulting in a subsequent change in glomerular filtration with an increase in serum creatinine and proteinuria levels (134). ADR also exacerbates fibrosis as indicated by an increase in the accumulation of extracellular matrix in the tubulointerstitium (5).…”