12 - Sex differences in kidney structure and function in a mouse model of intrauterine growth restriction

Poster Number: 12
Publication Number: 12.1665

Background: Low birth weight is associated with a greater risk for both acute and chronic kidney disease. In rodents, maternal protein restriction during gestation reproduces low birth weight offspring with many of the features of human disease and several sex differences have been described. However, most studies have been in rats and are limited to glomerular evaluations.

Objective: Our group’s long-term goal is to understand the effect of commonly used nephrotoxic medications on progression to CKD. To accomplish this goal, the objective of this study is to characterize differences in kidney morphology and function in the mouse model of maternal protein restriction and identify sex differences that may be important after kidney injury.

Design/Methods: Pregnant CD-1 dams were fed a normal protein (NP, 18%) or low protein (LP, 8%) diet from conception until gestation. LP litter size was matched to NP litter size with n=12/sex/diet group, based on sample size calculation. At weaning, LP and NP offspring were placed on the NP diet.
At 6 weeks of age, GFR was measured using transcutaneous measurement of fluorescein-isothiocyanate sinistrin. Kidneys were prepared for histologic evaluation of the following: glomerular density and size, podocyte density, atubular glomeruli fraction (ATG), and proximal tubule area (PT). Histologic sections were analyzed with Amira (Thermo Fisher Scientific software). Data were analyzed by Student’s t-test using Prism 9 (GraphPad software).

Results: When compared to female mice, males had larger kidney weight/body weight ratio (KW/BW), cortex area, and PT area, lower glomerular density, and fewer ATG. When compared to NP mice, LP mice had smaller KW/BW, fewer and smaller glomeruli, and smaller cortex area. There was no difference in glomerular and podocyte density amongst the groups. LP male mice had a lower GFR and more ATG compared to NP male mice, while females were similar. LP females had lower PT area, while males were similar.

Conclusion(s): Beyond the known glomerular differences in growth restriction models, we have also identified tubular differences that appear to be sex specific including more ATG in the LP males and less PT area in the LP females. This structural characterization will help in discerning the impact of acute kidney injury in the next step of the project.