Oxidative Stress and Cellular Senescence Are Involved in the Aging Kidney

Author:

Marquez-Exposito LauraORCID,Tejedor-Santamaria LuciaORCID,Valentijn Floris A.ORCID,Tejera-Muñoz AntonioORCID,Rayego-Mateos SandraORCID,Marchant Vanessa,Rodrigues-Diez Raul R.ORCID,Rubio-Soto Irene,Knoppert Sebastiaan N.,Ortiz AlbertoORCID,Ramos Adrian M.,Goldschmeding Roel,Ruiz-Ortega MartaORCID

Abstract

Chronic kidney disease (CKD) can be considered as a clinical model for premature aging. However, non-invasive biomarkers to detect early kidney damage and the onset of a senescent phenotype are lacking. Most of the preclinical senescence studies in aging have been done in very old mice. Furthermore, the precise characterization and over-time development of age-related senescence in the kidney remain unclear. To address these limitations, the age-related activation of cellular senescence-associated mechanisms and their correlation with early structural changes in the kidney were investigated in 3- to 18-month-old C57BL6 mice. Inflammatory cell infiltration was observed by 12 months, whereas tubular damage and collagen accumulation occurred later. Early activation of cellular-senescence-associated mechanisms was found in 12-month-old mice, characterized by activation of the DNA-damage-response (DDR), mainly in tubular cells; activation of the antioxidant NRF2 pathway; and klotho downregulation. However, induction of tubular-cell-cycle-arrest (CCA) and overexpression of renal senescent-associated secretory phenotype (SASP) components was only found in 18-month-old mice. In aging mice, both inflammation and oxidative stress (marked by elevated lipid peroxidation and NRF2 inactivation) remained increased. These findings support the hypothesis that prolonged DDR and CCA, loss of nephroprotective factors (klotho), and dysfunctional redox regulatory mechanisms (NRF2/antioxidant defense) can be early drivers of age-related kidney-damage progression.

Funder

Instituto de Salud Carlos III

Red de Investigación Renal REDINREN

Ministry of Economy, Industry and Competitiveness

Publisher

MDPI AG

Subject

Cell Biology,Clinical Biochemistry,Molecular Biology,Biochemistry,Physiology

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