MondoA and AKI and AKI-to-CKD Transition

Authors

Shihomi Maeda
Shinsuke Sakai
Yoshitsugu Takabatake
Takeshi Yamamoto
Satoshi Minami
Jun Nakamura
Tomoko Namba-Hamano
Atsushi Takahashi
Jun Matsuda
Hiroaki Yonishi
Sho Matsui
Atsuhiro Imai
Ryuya Edahiro
Hitomi Yamamoto-Imoto
Isao Matsui
Seiji Takashima
Ryoichi Imamura
Norio Nonomura
Motoko Yanagita
Yukinori Okada
Andrea Ballabio
Shuhei Nakamura
Tamotsu Yoshimori
Yoshitaka Isaka

Language

English

Publication Date

9-1-2024

Journal

Journal of the American Society of Nephrology

DOI

10.1681/ASN.0000000000000414

PMID

38819935

PMCID

PMC11387036

PubMedCentral® Posted Date

5-31-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Key Points:

1. The expression of MondoA was decreased in the renal tubules of patients with CKD.

2. Genetic ablation of MondoA in proximal tubules inhibited autophagy and increased vulnerability to AKI through increased expression of Rubicon.

3. MondoA ablation during the recovery phase after ischemia-reperfusion aggravated kidney injury through downregulation of the transcription factor EB-peroxisome proliferator-activated receptor-γ coactivator-1α axis.

Background: Elderly individuals and patients with CKD are at a higher risk of AKI. The transcription factor MondoA is downregulated in the kidneys of aged individuals or patients with AKI; however, its roles in AKI development and the AKI-to-CKD transition remain unknown.

Methods: We investigated the expression of MondoA in human kidney biopsy samples, ischemia-reperfusion–injured (IRI) mouse kidneys, and cultured proximal tubular epithelial cells under hypoxia/reoxygenation. The role of MondoA during the initial and recovery phases after IRI was evaluated using proximal tubule–specific MondoA knockout mice and MondoA-deficient proximal tubular epithelial cells. Furthermore, we explored the involvement of Rubicon and transcription factor EB (TFEB), both of which are downstream factors of MondoA.

Results: MONDOA expression was decreased in the renal tubules of patients with CKD. In mouse kidneys, MondoA expression was decreased under ischemia, whereas its expression was increased during reperfusion. Genetic ablation of MondoA in proximal tubular epithelial cells inhibited autophagy and increased vulnerability to AKI through increased expression of Rubicon. Ablation of Rubicon in MondoA-deficient IRI kidneys activated autophagy and protected mitochondrial function. MondoA ablation during the recovery phase after ischemia-reperfusion aggravated kidney injury through downregulation of the TFEB-peroxisome proliferator-activated receptor-γ coactivator-1α axis. Pharmacological upregulation of TFEB contributed to maintaining mitochondrial biogenesis and increased peroxisome proliferator-activated receptor-γ coactivator-1α transcription.

Conclusions: Our findings demonstrate that MondoA protected against vulnerability to AKI by maintaining autophagy and subsequently supporting mitochondrial function to prevent progression to CKD.

Keywords

AKI, CKD, fibrosis, hypoxia, ischemia-reperfusion, kidney biopsy, kidney tubule, mitochondria, molecular biology, transcription factors

Published Open-Access

yes

Recommended Citation

Maeda, Shihomi; Sakai, Shinsuke; Takabatake, Yoshitsugu; et al., "MondoA and AKI and AKI-to-CKD Transition" (2024). Duncan NRI Faculty and Staff Publications. 134.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/134