TFEB drives ER stress-induced apoptosis and limits cyst growth in polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of renal cysts and loss of renal function. Here, it was demonstrated that transcription factor EB (TFEB) activation in cyst-lining epithelial cells enhances their susceptibility to apoptosis via endoplasmic reticulum (ER) stress-induced signaling, ultimately restricting cyst expansion. Single-cell RNA sequencing in Pkd1 -deficient mouse models identified G-protein coupled receptor family C group 5 member A (GPRC5A)-positive cyst-lining cell clusters originating from the loop of Henle and proximal tubules. These cells exhibited dysregulated Hippo signaling and enhanced unfolded protein response (UPR). With this change in UPR, nuclear localization of TFEB and C/EBP homologous protein (CHOP) was observed, and expression of pro-apoptotic target genes of CHOP, such as Ppp1r15 and Pmaip1 , increased. TFEB deficiency attenuated apoptosis, resulting in accelerated cyst growth. Human ADPKD kidney samples mirrored these findings, showing nuclear TFEB and CHOP accumulation in cyst-lining cells. These results indicated that TFEB is a key modulator of ER stress-induced apoptosis in cyst-lining cells, suggesting that TFEB activation paradoxically limits cyst expansion through apoptosis in ADPKD.

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BibTeX

@article{nakamura2026tfeb,
  title = {{TFEB drives ER stress-induced apoptosis and limits cyst growth in polycystic kidney disease}},
  author = {Jun Nakamura and Sho Matsui and Takeshi Yamamoto and Hideaki Kawai and Takuya Kubota and Yoshitsugu Takabatake and Tomoko Namba-Hamano and Atsushi Takahashi and Satoshi Minami and Shinsuke Sakai and Hiroaki Yonishi and Isao Matsui and Gaku Yamamichi and Taigo Kato and Shun Takenaka and Norio Nonomura and Saori Nishio and Tamotsu Yoshimori and Yoshitaka Isaka},
  journal = {Scientific Reports},
  year = {2026},
  month = oct,
  doi = {10.1038/s41598-026-71412-6},
  url = {https://www.nature.com/articles/s41598-026-71412-6},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - TFEB drives ER stress-induced apoptosis and limits cyst growth in polycystic kidney disease
AU  - Jun Nakamura
AU  - Sho Matsui
AU  - Takeshi Yamamoto
AU  - Hideaki Kawai
AU  - Takuya Kubota
AU  - Yoshitsugu Takabatake
AU  - Tomoko Namba-Hamano
AU  - Atsushi Takahashi
AU  - Satoshi Minami
AU  - Shinsuke Sakai
AU  - Hiroaki Yonishi
AU  - Isao Matsui
AU  - Gaku Yamamichi
AU  - Taigo Kato
AU  - Shun Takenaka
AU  - Norio Nonomura
AU  - Saori Nishio
AU  - Tamotsu Yoshimori
AU  - Yoshitaka Isaka
PY  - 2026
DA  - 2026/10/14
JO  - Scientific Reports
DO  - 10.1038/s41598-026-71412-6
UR  - https://www.nature.com/articles/s41598-026-71412-6
AB  - Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of renal cysts and loss of renal function. Here, it was demonstrated that transcription factor EB (TFEB) activation in cyst-lining epithelial cells enhances their susceptibility to apoptosis via endoplasmic reticulum (ER) stress-induced signaling, ultimately restricting cyst expansion. Single-cell RNA sequencing in Pkd1 -deficient mouse models identified G-protein coupled receptor family C group 5 member A (GPRC5A)-positive cyst-lining cell clusters originating from the loop of Henle and proximal tubules. These cells exhibited dysregulated Hippo signaling and enhanced unfolded protein response (UPR). With this change in UPR, nuclear localization of TFEB and C/EBP homologous protein (CHOP) was observed, and expression of pro-apoptotic target genes of CHOP, such as Ppp1r15 and Pmaip1 , increased. TFEB deficiency attenuated apoptosis, resulting in accelerated cyst growth. Human ADPKD kidney samples mirrored these findings, showing nuclear TFEB and CHOP accumulation in cyst-lining cells. These results indicated that TFEB is a key modulator of ER stress-induced apoptosis in cyst-lining cells, suggesting that TFEB activation paradoxically limits cyst expansion through apoptosis in ADPKD.
SN  - 2045-2322
ER  -

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