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ABSTRACT
Autophagy plays an essential role in cellular homeostasis through the quality control of proteins and organelles. Although a time-dependent decline in autophagic activity is believed to be involved in the aging process, the issue remains controversial. We previously demonstrated that autophagy maintains proximal tubular cell homeostasis and protects against kidney injury. Here, we extend that study and examine how autophagy is involved in kidney aging. Unexpectedly, the basal autophagic activity was higher in the aged kidney than that in young kidney; short-term cessation of autophagy in tamoxifen-inducible proximal tubule-specific autophagy-deficient mice increased the accumulation of SQSTM1/p62- and ubiquitin-positive aggregates in the aged kidney. By contrast, autophagic flux in response to metabolic stress was blunted with aging, as demonstrated by the observation that transgenic mice expressing a green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3B fusion construct, showed a drastic increase of GFP-positive puncta in response to starvation in young mice compared to a slight increase observed in aged mice. Finally, proximal tubule-specific autophagy-deficient mice at 24 mo of age exhibited a significant deterioration in kidney function and fibrosis concomitant with mitochondrial dysfunction as well as mitochondrial DNA abnormalities and nuclear DNA damage, all of which are hallmark characteristics of cellular senescence. These results suggest that age-dependent high basal autophagy plays a crucial role in counteracting kidney aging through mitochondrial quality control. Furthermore, a reduced capacity for upregulation of autophagic flux in response to metabolic stress may be associated with age-related kidney diseases.
Abbreviations
| ACTB | = | actin, beta |
| ACAC | = | acetyl-CoA carboxylase |
| AMPK | = | AMP-activated protein kinase |
| Atg | = | autophagy-related |
| CKD | = | chronic kidney disease |
| CML | = | N-carboxymethyllysine |
| COL1A1 | = | collagen type I alpha 1 |
| COX | = | cytochrome c oxidase |
| COX4I1 | = | cytochrome c oxidase subunit IV isoform 1 |
| GFP | = | green fluorescent protein |
| HAVCR1/Kim-1 | = | hepatitis A virus cellular receptor 1 |
| H2AFX | = | H2A histone family, member X |
| HNE | = | 4-hydroxy-2-nonenal |
| KAP | = | kidney androgen regulated protein |
| LCN2/Ngal | = | lipocalin 2 |
| LRP2 | = | low density lipoprotein receptor-related protein 2 |
| MAP1LC3B/LC3 | = | microtubule-associated protein 1 light chain 3B |
| MKI67 | = | antigen identified by monoclonal antibody Ki67 |
| MT-CO1 | = | mitochondrially encoded cytochrome c oxidase I |
| mtDNA | = | mitochondrial DNA |
| MTOR | = | mechanistic target of rapamycin (serine/threonine kinase) |
| NDRG1 | = | N-myc downstream regulated gene 1 |
| NDUFV1 | = | NADH:ubiquinone oxidoreductase core subunit V1 (formerly also termed NADH dehydrogenase (ubiquinone) flavoprotein 1) |
| nDNA | = | nuclear DNA |
| PAS | = | periodic-acid Schiff |
| ROS | = | reactive oxygen species |
| RPS6 | = | ribosomal protein S6 |
| SA | = | senescence-associated |
| SDH | = | succinate dehydrogenase complex |
| SIRT1 | = | sirtuin 1 |
| SQSTM1 | = | sequestosome 1 |
Disclosure of potential conflicts of interest
The authors declare that they have no conflict of interest.
Acknowledgments
We thank N. Mizushima, University of Tokyo, for Atg5F/F and GFP-MAP1LC3B transgenic mice; T. Michigami, Osaka Medical Center and Research Institute, for LRP2/MEGALIN antibody; and N. Horimoto, K. Shibayama, M. Kameda, and M. Nishio for technical and secretary assistance.
Funding
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan (22590890 [to H.K.], 24591196 [to Y.T.], and 24659416 [to Y.I.]), Takeda Medical Research Foundation [to Y.T.], Manpei Suzuki Diabetes Foundation [to T.K.] and Uehara Memorial Foundation [to T.K.].