Abstract
Podocyte injury and loss contribute to proteinuria, glomerulosclerosis, and eventually kidney failure. Activating transcription factor 3 (ATF3) is a stress inducible transcription factor that is transiently expressed following stimulation. However, we show for the first time an induction of ATF3 in podocytes from patients with chronic kidney disease, including minimal change disease, focal segmental glomerulosclerosis, and diabetic nephropathy. The role of ATF3 induction in podocytes under chronic conditions is currently unknown. Compared with the control (C57 or BKS), ATF3 expression was elevated in animal model of proteinuria (LPS-treated C57 mice) and the model of diabetic nephropathy (db/db mice). Similarly, ATF3 was increased in high glucose (HG)-treated, lipopolysaccharide (LPS)-treated, or Ionomycin-treated podocytes in vitro. Overexpression of ATF3 increased podocyte apoptosis and decreased expression of podocin, the cell marker of podocyte; in contrast, ATF3–small interfering RNA knockdown reduced podocyte apoptosis and increased podocin expression. The translocation of ATF3 to the nucleus was increased upon stimulation. ATF3 directly modulates the regulation of NFATc1 gene promoter activity and alters the expression of Wnt6 and Fzd9, direct target genes of NFATc1 signaling. The ATF3 binding site of NFATc1 gene promoter is located at the region 671–775 base pairs upstream of the transcription start site. These results indicate a novel inducible axis of ATF3–NFAT in podocyte injury and loss.Key messages• The stress factor ATF3 is induced in podocytes from proteinuric patients, including diabetes.• ATF3 increased podocyte apoptosis and injury.• ATF3 directly modulates the regulation of NFATc1 gene promoter activity.
Highlights
Podocyte injury and loss contribute to proteinuria and progressive glomerulosclerosis [1,2,3]
Activating transcription factor 3 (ATF3) was increased in glomeruli from proteinuric patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and diabetic nephropathy (DN)
We found low-level ATF3 protein in individuals without glomerular disease (Fig. 1b); in contrast, patients with MCD, FSGS, or DN had a significant increase in ATF3 protein, and an even stronger ATF3 expression was found in glomeruli cells from DN patients (Fig. 1b)
Summary
Podocyte injury and loss contribute to proteinuria and progressive glomerulosclerosis [1,2,3]. Mutation and abnormalities in the slit diaphragm proteins in junctional domain (podocin, nephrin, CD2AP, and others) are associated with podocyte injury and loss, proteinuria, and glomerulosclerosis [5,6,7]. Podocytes play such a key role in maintaining the structural and functional integrity of the filtration barrier that the progression of kidney disease always has podocyte involvement [8]. There is evidence that apoptosis contributes to podocyte loss [9].
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