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Kidney Week

Abstract: FR-PO145

Caspase-3 Activation Increases with Age and Aggravates Kidney Injury After Ischemia-Reperfusion

Session Information

  • AKI: Mechanisms - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Kaci, Imane, Universite de Montreal, Montreal, Quebec, Canada
  • Lan, Shanshan, Universite de Montreal, Montreal, Quebec, Canada
  • Kim, Hyunyun, Universite de Montreal, Montreal, Quebec, Canada
  • Karakeussian Rimbaud, Annie, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Migneault, Francis, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Turgeon, Julie, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
  • Patey, Natalie, Universite de Montreal, Montreal, Quebec, Canada
  • Dieudé, Mélanie, Universite de Montreal, Montreal, Quebec, Canada
  • Hebert, Marie-Josee, Universite de Montreal, Montreal, Quebec, Canada
Background

Rarefaction of peritubular capillaries (PTC) after ischemia-reperfusion injury (IRI) predicts progressive renal failure, especially in older kidneys. We previously demonstrated the importance of caspase-3-dependent microvascular damage in progressive kidney dysfunction after IRI. We also showed that renal IRI increases circulating levels of ApoExo; an immunogenic type of exosome-like vesicles produced by apoptotic endothelial cells downstream of caspase-3 activation, and characterized by the presence of LG3/perlecan autoantigen and active 20S proteasome. Here, we hypothesize that age modulates caspase-3 activation after renal IRI leading to increased release of ApoExo, enhanced PTC rarefaction, fibrosis and renal dysfunction.

Methods

Unilateral renal pedicle clamping (30 minutes) and contralateral nephrectomy were performed in young (8 weeks-old) and old (27 and 53 weeks-old) mice. ApoExo were purified from serum-free medium conditioned by apoptotic murine endothelial cells in vitro and injected to mice via tail vein every other day. Endpoints were assessed 21 days post-IRI. ApoExo circulating levels were measured by proteasome activity and anti-LG3 titers by ELISA. Complement deposition, caspase-3 activation, PTC rarefaction and fibrosis were assessed by immunohistochemistry. Renal function was monitored by BUN level.

Results

At baseline, old mice showed higher levels of caspase-3 activation within PTC, lower PTC density and higher anti-LG3 titers. Renal IRI led to significant increase in PTC caspase-3 activation, ApoExo and anti-LG3 circulating levels with age. PTC C4d deposition, interstitial fibrosis and renal function were worsened by age. To test the role of ApoExo in fueling maladaptive responses to IRI, young mice were injected with ApoExo to reach circulating levels observed in old mice. ApoExo injection increased anti-LG3 formation, PTC C4d deposition, caspase-3 activation, PTC rarefaction and interstitial fibrosis, and aggravated renal dysfunction.

Conclusion

Our results suggest that caspase-3 activation within PTC increases with older age leading to more ApoExo production post-IRI. The latter enhances microvascular damage and fibrosis, favoring progressive kidney dysfunction.

Funding

  • Private Foundation Support