Abstract: SA-OR19
Neonatal Fc Receptor: More than a Transcytosis Receptor
Session Information
- CKD: New Insights into Mechanisms and Treatment Strategies
October 26, 2024 | Location: Room 24, Convention Center
Abstract Time: 04:30 PM - 04:40 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Dahlke, Eileen, CAU Kiel Institute of Anatomy, Kiel, Germany
- Anan, Yaman, CAU Kiel Institute of Anatomy, Kiel, Germany
- Mittag, Jan-Hendrik, CAU Kiel Institute of Anatomy, Kiel, Germany
- Klie, Lea, CAU Kiel Institute of Anatomy, Kiel, Germany
- Hartkopf, Ariane, CAU Kiel Institute of Anatomy, Kiel, Germany
- Theilig, Franziska, CAU Kiel Institute of Anatomy, Kiel, Germany
Background
Chronic kidney disease (CKD) increases worldwide and is a high social economic burden. Diabetic kidney disease is the leading cause for the development of CKD. GWAS studies presented a strong association between the neonatal Fc receptor (FcRn) and high fructosamin levels in diabetes mellitus. Previously, we found a strong FcRn mRNA reduction in STZ-treated type 1 diabetic mice. The role of FcRn decline in the progression towards CKD remain unknown.
Methods
3-, 6- and 15-month-old mice lacking FcRn (FcRn-/-) in comparison to wildtype mice (WT) were analyzed. Renal functional parameters and morphology were analyzed, immunohistological stainings, RNA sequencing and western blot analyses were performed. CRISPR/Cas9 FcRn knockout in BN16 yolk sac cells were used for western blotting, immunocytological and seahorse cellular respiration analyses, in addition to fructosamin treatment.
Results
A reduction in FcRn expression could be induced in vitro by treating BN16 cells (expressing FcRn endogeneously) with fructosamin. In vivo, deletion of FcRn leads to a significant reduction in the glomerular filtration rate in 3-month-old mice. After 6 month a significant reduction of renal cortices in FcRn-/- was observed and progressed over time due to shortening of proximal tubules, which was accompanied by reduced endocytosis capacity. The number of Ki-67 positive proximal tubule (PT) and endothelial cells was significantly reduced in FcRn-/- compared to WT mice. In addition, the area of the lysosomal compartment and connective tissue increased. RNAseq analysis revealed altered genes important for autophagy and ciliogenesis. An elongation of cilia in PT of FcRn-/- was confirmed immunohistologically. FcRn-/- CRISPR/Cas9 knockout cells confirm reduced proliferation and elevated autophagic flux and a higher oxygen consumption. Additionally, FcRn deletion leads to activation of mTORC1, lysomal protein expression (Lamp2), amino acid and ion transporter (B0AT1, Lat2, Lat4, NBC1).
Conclusion
In conclusion, loss of FcRn results in a switch of cellular metabolism with enhanced autophagy and respiration combined with proximal tubule reduction and functional impairment. Therefore, loss of FcRn results in a decline in kidney function mirroring some features of CKD and could contribute to the progression of DN towards CKD in diabetes mellitus.