94 - Co-localization of Angiotensin and Transferrin Receptors via Multiligand Receptor Megalin in Growth-Restricted Fetal Sheep Kidneys.

Poster Number: 94
Publication Number: 94.138

Henry A. Zapata Galarza, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; Hailey Prosek, University of Wisconsin School of Medicine and Public Health, Winneconne, WI, United States; NITHIN V. RAMACHANDRAN, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; Pawan K. Shahi, UW-Madison, MADISON, WI, United States; Bikash R. Pattnaik, University of Wisconsin, Madison, WI, United States; Matthew W. Harer, University of Wisconsin, Middleton, WI, United States; Ronald R. Magness, Univ South Florida, Tampa, FL, United States; Pamela J. Kling, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States

Background: Intrauterine growth restriction (IUGR) may impair nephrogenesis and lead to hyperfiltration, microproteinuria, hypertension, and progression to chronic kidney disease. We previously reported altered renal development, abnormal iron signaling, and higher cortical renin-angiotensin system (RAS) receptor expression in a multifetal IUGR sheep model compared with singleton controls. Altered renal iron handling via the transferrin receptors (TfR) may play a role in understanding RAS signaling mechanisms. RAS receptors and TfR may colocalize at epithelial surfaces with megalin, a chaperone multiligand endocytic receptor, that enhances absorption efficiency of ligand-receptor complexes from the glomerular ultrafiltrate. Therefore, we hypothesized that multifetal IUGR alters the colocalization of renal tubular RAS receptors and TfR via the megalin pathway.

Objective: To determine the impact of IUGR on renal tubular colocalization of RAS receptors or TfR via multiligand receptor, megalin, in a late gestation multifetal sheep model.

Design/Methods: Total of 124 fetal sheep were analyzed. Fetal sheep kidneys were collected at gestational day (GD) 130, term being GD 147, from IUGR and control fetuses. Multichannel immunofluorescent confocal microscopy localized expression of RAS receptors (AT1R, AT2R, MASR), TfR and megalin in 7 sheep with IUGR and 7 controls. Pearson’s coefficients were generated for each antibody combination (megalin with either AT1R, AT2R, MASR or TfR) using Nikon NIS- Element-AR Software. The Kruskal-Wallis and Mann-Whitney U tests were performed.

Results: Overall fetal sheep weight (p < 0.001) and kidney weight (p < 0.001) were lower in IUGR. Fetal blood urea nitrogen/creatinine ratio (p=0.063), iron level (p=0.22) and fetal/maternal iron level (p=0.16) trended lower, while fetal creatinine (p < 0.001), fetal/maternal creatinine (p =0.002), total iron binding capacity (p=0.19) trended higher in IUGR. The strength of correlation between RAS receptors or TfR and megalin expression did not differ between IUGR vs control fetuses. AT1R (R2=0.45 vs 0.45, p=0.9), AT2R (R2=0.4 vs 0.46, p=0.5), MASR (R2=0.2 vs 0.32, p=0.5), and TfR (R2=0.53 vs 0.64, p=0.12).Conclusion(s): In this study, we find no significant differences in colocalization of RAS receptors or TfR with megalin in proximal tubules in this multi-fetal IUGR fetal sheep model. To understand the mechanisms behind altered RAS and iron receptors, future work should examine colocalization in the distal tubules and collecting duct levels, in addition to the role of other multiligand receptors.
Henry Zapata CV 2022.pdf