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Kidney Week

Abstract: TH-PO555

Aging Aggravates Oxidation Processes and Collagen Accumulation in the Experimental AKI-to-CKD Transition

Session Information

  • Pathology and Lab Medicine
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pathology and Lab Medicine

  • 1700 Pathology and Lab Medicine

Authors

  • Marquez-Exposito, Laura, Universidad Autonoma de Madrid, IIS-FJD, Madrid, Spain
  • Tejedor, Lucia, Universidad Autonoma de Madrid, IIS-FJD, Madrid, Spain
  • Valentijn, Floris, University Medical Center Utrecht, Utrecht, Netherlands
  • Marchant, Vanessa, Universidad Autonoma de Madrid, IIS-FJD, Madrid, Spain
  • Goldschmeding, Roel, University Medical Center Utrecht, Utrecht, Netherlands
  • Ruiz-Ortega, Marta, Universidad Autonoma de Madrid, IIS-FJD, Madrid, Spain
Background

Chronic kidney disease (CKD) is very frequent in aged patients, being associated to a high mortality. Our group has previously described a dysfunctional redox-regulated mechanisms and an early activation of cellular senescence in 1 year old C57BL6 mice. Moreover, in folic acid (FA)-induced Acute Kidney Injury (AKI) in these mice, exacerbation of tubular injury, necroinflammation and cellular senescence was observed. However, mechanisms leading to AKI-to-CKD transition in the aging are completely unknown.

Methods

A single low-dose of FA (125mg/kg) were injected to young (3 months) and aged (12 months) mice and kidneys were studied after 10 days.

Results

First, a Kaplan-Meier curve showed a 91% of survival in the FA-young group, whereas only a 46% of FA-aged group survived. The higher mortality in aging mice was observed at day 8 corresponding to the AKI-to-CKD transition phase. The PAS staining in survival mice showed higher inflammatory infiltrating cells in FA-aged mice compared to FA-young mice, but tubular dilatation and renal dysfunction were similar between groups. The assessment of cellular senescence mechanisms through the activation of DNA-Damage Responses, such as phosphorylation of H2AX histone and the cycline-dependent kinase inhibitors, such as p21cip1 and p16ink4a, demonstrated not significant differences between FA-damaged groups. On the contrary, gene expression levels of several Senescence-Associated Secretory Phenotype, such as Ccn2, and the proinflammatory factors Tnfa and Ccl5, were found augmented in FA-aged mice. Collagen accumulation, evaluated by a picrosirius red staining, showed higher deposition in FA-aged mice. Moreover, LOX and LOXL2 protein levels were significantly increased in FA-aged mice. On the other hand, NRF2 antioxidant protein evaluation and total protein nitration by 3-nitrotyrosine, showed an increase in the FA-aged mice, demonstrating an deregulation in the cellular oxidation and antioxidant response associated to aging in these mice.

Conclusion

Our study showed that AKI-to-CKD transition in aging mice is characterized by increased mortality, inflammatory cell infiltration and kidney fibrosis. The mechanisms involved in increased susceptibility to CKD progression might be mediated by deregulation of redox processes and sustained inflammation.

Funding

  • Government Support – Non-U.S.