Abstract: PO0400
Apoptotic Exosome-Like Vesicles Aggravate Inflammation and Renal Injury After Ischemia-Reperfusion
Session Information
- AKI: Repair and Progression
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Kaci, Imane, Universite de Montreal Faculte de Medecine, Montreal, Quebec, Canada
- Lan, Shanshan, Universite de Montreal Faculte de Medecine, Montreal, Quebec, Canada
- Kim, Hyunyun, Universite de Montreal Faculte de Medecine, Montreal, Quebec, Canada
- Karakeussian Rimbaud, Annie, Centre Hospitalier de l'Universite de Montreal Centre de Recherche, Montreal, Quebec, Canada
- Migneault, Francis, Centre Hospitalier de l'Universite de Montreal Centre de Recherche, Montreal, Quebec, Canada
- Turgeon, Julie, Centre Hospitalier de l'Universite de Montreal Centre de Recherche, Montreal, Quebec, Canada
- Patey, Natalie, Centre Hospitalier Universitaire Sainte-Justine Centre de Recherche, Montreal, Quebec, Canada
- Dieudé, Mélanie, Centre Hospitalier de l'Universite de Montreal Centre de Recherche, Montreal, Quebec, Canada
- Hebert, Marie-Josee, Centre Hospitalier de l'Universite de Montreal Centre de Recherche, Montreal, Quebec, Canada
Background
Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) and chronic kidney disease (CKD). Mounting evidence suggests that damage to microvascular peritubular capillaries (PTC) is a critical determinant of CKD transition after IRI. We previously identified anti-LG3/perlecan autoantibodies in patients with CKD, as a negative prognostic factor for long-term renal function after AKI. We also showed that a new class of extracellular vesicles produced by apoptotic endothelial cells (ApoExo), characterized by the LG3 autoantigen, active 20S proteasome and a specific pattern of immunogenic RNAs, can prompt the production of anti-LG3. Here, we test the hypothesis that ApoExo drive renal inflammation after renal IRI leading to anti-LG3 production, defective microvascular repair and loss of renal function.
Methods
ApoExo were purified by sequential ultracentrifugation from serum-free media conditioned by apoptotic murine endothelial cells. Renal IRI in mice was performed with renal artery clamping for 30 minutes and contralateral nephrectomy. ApoExo were injected twice every other day before IRI and thereafter up to eight injections, and end-points were assessed at day 21 post-IRI. Interstitial inflammation was assessed with immunohistochemistry for CD3 and IL-17A. PTC rarefaction, complement activation and myofibroblasts accumulation were monitored by immunohistochemistry for MECA-32, C4d and α-SMA. Circulating anti-LG3 levels were measured by ELISA.
Results
ApoExo injection enhanced tubular damage and interstitial inflammation with increased CD3+ lymphocytes infiltration and IL-17A staining (p=0.004 and p=0.002, respectively). PTC rarefaction, C4d deposition and interstitial accumulation of α-SMA+ cells were also increased in ApoExo treated mice (p=0.01, p=0.009 and p=0.04, respectively) as were anti-LG3, which correlated strongly and positively with PTC-C4d deposition and myofibroblasts accumulation (r=0.86, p=0.007 and r=0.75, p=0.03, respectively).
Conclusion
Collectively, these results identify ApoExo as novel regulators of inflammation after renal IRI, driving anti-LG3 formation, complement activation and fibrosis. These results suggest that autoimmune pathways triggered by ApoExo can contribute to microvascular rarefaction and renal fibrosis.
Funding
- Private Foundation Support