Atonal BHLH transcription factor 8 ( ATOH8) is a basic helix-loop-helix (bHLH) transcription factor; however, its role in glomerular epithelial cells (podocytes) remains unclear. This study aimed to elucidate the function of ATOH8 in podocytes. First, ATOH8 expression in the mouse kidney was confirmed in podocytes by immunofluorescence staining and in situ hybridization. In cultured human podocytes, transforming growth factor-beta (TGF-β) treatment significantly reduced ATOH8 mRNA expression. To examine the functional consequences of ATOH8 downregulation, ATOH8 expression was knocked down using shRNA. Subsequent RNA sequencing analysis of ATOH8-knockdown podocytes revealed increased extracellular matrix gene expression and activation of TGF-β signaling. ATOH8-knockdown podocytes also showed SMAD2/3 nuclear translocation, increased SMAD transcriptional activity, as determined by a luciferase assay, and upregulated TGFB1 mRNA even without TGF-β stimulation, consistent with TGF-β signaling activation. In vivo, C57BL/6 Atoh8-deficient mice showed no renal abnormalities at baseline. However, in an adriamycin (ADR)-induced focal segmental glomerulosclerosis (FSGS) model, Atoh8-deficient mice developed significantly more severe glomerulosclerosis than wild-type mice, with higher renal cortical Tgfb1 and Col4a1 mRNA levels. Reduced ATOH8 expression was also observed in ADR-induced nephropathy in mice and rats and in various human glomerular diseases. These findings suggest that ATOH8 downregulation enhances TGF-β signaling and glomerulosclerosis progression, indicating a protective role for ATOH8 in maintaining podocyte i 77 ntegrity and preventing kidney injury.
Hamatani et al. (Fri,) studied this question.