Signs of Premature Kidney Aging in Mice With Error-Prone Protein Synthesis
Laurine Lang1, Rocío Fuente2,3, José Manuel López3
1Institute of Physiology, University of Zurich, Zurich, Switzerland.
Summary
Protein translation errors accelerate aging in mammals. Mice with faulty translation show premature kidney aging, including fibrosis and dysfunction, suggesting a link between protein errors and kidney disease.
Area of Science:
- Nephrology
- Aging Biology
- Molecular Biology
Background:
- Chronic kidney disease (CKD) incidence rises with age, driven by hypertension, diabetes, and age-related kidney function decline.
- Understanding kidney aging mechanisms is crucial for managing CKD and promoting healthy aging.
- Protein translation errors have been identified as a factor accelerating aging in mammals.
Purpose of the Study:
- To investigate the impact of genome-wide error-prone translation on kidney aging.
- To identify specific kidney alterations and functional changes associated with translation errors.
Main Methods:
- Deep phenotyping of Rps9D95N/+ mice with ribosomal ambiguity mutation.
- Analysis of renal histology, autophagy markers, fibrosis, and kidney injury markers (e.g., albuminuria, Kim-1).
- RNA sequencing and targeted metabolomic analysis to assess lipid and phosphate metabolism.
Main Results:
- Rps9D95N/+ mice exhibited premature kidney aging signs: renal amyloidosis, altered glomerular basement membrane, reduced autophagy, and renal fibrosis.
- Kidney dysfunction was evident through albuminuria and elevated Kim-1 levels.
- Altered lipid metabolism with increased lipid deposition was observed, while systemic phosphate metabolism showed only mild changes.
Conclusions:
- Genome-wide error-prone translation accelerates kidney aging and contributes to kidney dysfunction.
- Accelerated loss of proteostasis due to translation errors is a likely mechanism driving premature kidney aging.
- These findings offer insights into the molecular basis of kidney aging and potential therapeutic targets for CKD.
