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ABSTRACT
Chronic kidney disease (CKD) has reached epidemic proportions worldwide, partly due to the increasing population of elderly and obesity. Macroautophagy/autophagy counteracts CKD progression, whereas autophagy is stagnated owing to lysosomal overburden during aging and obesity, which promotes CKD progression. Therefore, for preventing CKD progression during aging and obesity, it is important to elucidate the compensation mechanisms of autophagy stagnation. We recently showed that FGF21 (fibroblast growth factor 21), which is a prolongevity and metabolic hormone, is induced by autophagy deficiency in kidney proximal tubular epithelial cells (PTECs); however, its pathophysiological role remains uncertain. Here, we investigated the interplay between FGF21 and autophagy and the direct contribution of endogenous FGF21 in the kidney during aging and obesity using PTEC-specific fgf21- and/or atg5-deficient mice at 24 months (aged) or under high-fat diet (obese) conditions. PTEC-specific FGF21 deficiency in young mice increased autophagic flux due to increased demand of autophagy, whereas fgf21-deficient aged or obese mice exacerbated autophagy stagnation due to severer lysosomal overburden caused by aberrant autophagy. FGF21 was robustly induced by autophagy deficiency, and aged or obese PTEC-specific fgf21- and atg5-double deficient mice deteriorated renal histology compared with atg5-deficient mice. Mitochondrial function was severely disturbed concomitant with exacerbated oxidative stress and downregulated TFAM (transcription factor A, mitochondrial) in double-deficient mice. These results indicate that FGF21 is robustly induced by autophagy disturbance and protects against CKD progression during aging and obesity by alleviating autophagy stagnation and maintaining mitochondrial homeostasis, which will pave the way to a novel treatment for CKD.
Abbreviations
| ACTB | = | actin, beta |
| ADGRE1/F4/80 | = | adhesion G protein-coupled receptor E1 |
| AKI | = | acute kidney injury |
| AMPK | = | AMP-activated protein kinase |
| ATF4 | = | activating transcription factor 4 |
| ATG | = | autophagy related |
| ChAT | = | chloramphenicol acetyltransferase |
| CDKN1A/p21cip1 | = | cyclin dependent kinase inhibitor 1A |
| CDKN2A/p19Arf | = | cyclin dependent kinase inhibitor 2A |
| CKD | = | chronic kidney disease |
| CML | = | N-carboxymethyllysine |
| COL1A1 | = | Collagen, type I, alpha 1 |
| COX | = | cytochrome c oxidase |
| CRE | = | creatinine |
| CTRL | = | control |
| DDIT3/CHOP | = | DNA-damage inducible transcript 3 |
| DNAJB9/ERDJ4 | = | DnaJ heat shock protein family (Hsp40) member B9 |
| EGFP | = | enhanced green fluorescent protein |
| ER | = | endoplasmic reticulum |
| FGF21 | = | fibroblast growth factor 21 |
| GAPDH | = | glyceraldehyde-3-phosphate dehydrogenase |
| GFP | = | green fluorescent protein |
| HAVCR1/KIM-1 | = | hepatitis A virus cellular receptor 1 |
| HFD | = | high-fat diet |
| HNE | = | 4-hydroxy-2-nonenal |
| HSPA5/BIP | = | heat shock protein 5 |
| KAP | = | kidney androgen regulated protein |
| LAMP1 | = | lysosomal-associated membrane protein 1 |
| LCN2/NGAL | = | lipocalin 2 |
| LRP2 | = | low density lipoprotein receptor-related protein 2 |
| MAP1LC3B/LC3 | = | microtubule-associated protein 1 light chain 3 beta |
| mitoISR | = | mitochondrial integrated stress response |
| MTORC1 | = | mechanistic target of rapamycin kinase complex 1 |
| NAD | = | nicotinamide adenine dinucleotide |
| NAMPT | = | nicotinamide phosphoribosyltransferase |
| PAS | = | periodic-acid schiff |
| PPARGC1/PGC1 | = | peroxisome proliferative activated receptor, gamma, coactivator 1 |
| PTEC | = | proximal tubular epithelial cell |
| ROS | = | reactive oxygen species |
| RPS6 | = | ribosomal protein S6 |
| SDH | = | succinate dehydrogenase complex |
| SIRT1 | = | sirtuin 1 |
| SOD | = | superoxide dismutase |
| SQSTM1/p62 | = | sequestosome 1 |
| TFAM | = | transcription factor A, mitochondrial |
| TGFB/TGFβ | = | transforming growth factor, beta |
| TSDKO | = | tissue-specific double knockout |
| TSKO | = | tissue-specific knockout |
| UCP | = | uncoupling protein (mitochondrial, proton carrier) |
| phospho-H2AFX/γ-H2AX | = | phosphorylated H2A.X variant histone |
| XBP1s | = | X-box binding protein 1; spliced form |
Acknowledgements
We thank N. Mizushima, University of Tokyo, for Atg5F/F and GFP-MAP1LC3B mice; T. Matsusaka and F. Niimura, Tokai University School of Medicine, for KAP-Cre mice; T. Michigami, Osaka Medical Center and Research Institute, for LRP2/MEGALIN antibody; and N. Horimoto for technical assistance.
Disclosure statement
No potential conflict of interest was reported by the authors.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2023.2259282