029 - Sex Differences in Kidney Structural Alterations in a Hyperglycemic Preterm Mouse Model.

Publication Number: 29.6796

Rachel K. Dailey, University of Virginia School of Medicine, Gloucester, MA, United States; Aleksandra Cwiek, University of Virginia, Charlottesville, VA, United States; Kimberly deRonde, un, Charlottesville, VA, United States; Jaya Isaac, The Children's Hospital at Montefiore, Bronx, NY, United States; Ayyappa Kumar Sista Kameshwar, Texas A&M University, College station, TX, United States; Kevin Bennett, Washington University in St. Louis School of Medicine, St. Louis, MO, United States; Masako Suzuki, Texas A&M University, College Station, TX, United States; Kimberly J. Reidy, The Children's Hospital at Montefiore, Bronx, NY, United States; Jennifer R Charlton, University of Virginia School of Medicine, charlottesville, VA, United States

Background: Preterm birth is a significant risk factor for chronic kidney disease (CKD) and diabetes mellitus. In adults, diabetic kidney disease (DKD) is the leading cause of CKD and sex differences likely influence DKD progression. To study the effect of second hits such as diabetes following preterm birth, we have established a mouse model of preterm birth and induced hyperglycemia during adulthood. We previously performed a stratified analysis focusing on the males and found significant structural and molecular differences between preterm mice with diabetes compared to term mice with diabetes.

Objective: 1) Determine the effect of preterm birth in female mice with diabetes. 2) Identify sex differences in structural changes in the kidneys of term and preterm mice with diabetes.

Design/Methods: Preterm and term CD-1 pups were aged to 6 wks. Hyperglycemia was induced with streptozotocin from 6-18 wks creating the following groups: term-no diabetes (T-ND), preterm-no diabetes (PT-ND), term-diabetes (T-D), and preterm-diabetes (PT-D). Body weights and serum glucose levels were measured. We measured glomerular density and proximal tubular (PT) area histologically. Evaluation of podocyte density, glomerular number, and gene expression in the kidneys is ongoing.

Results: The effect of preterm birth in the diabetic females, highlighted in red in the Table, was less overt than in males. In females, PT fraction was lower in PT-D compared to the T-D mice. There were several notable sex differences. Females had significantly lower body weights and lower total kidney weights. Interestingly, the females had a significantly greater glomerular density across all groups, despite only a smaller cortical area in PT-D. KW/BW was only 17% higher in PT-D than PT-ND females, whereas it was 65% higher in PT-D than PT-ND males. PT-D females had a lower KW/BW ratio than PT-D males.

Conclusion(s): Female mice born one-day preterm appear more resistant than males to structural alterations in the kidney after hyperglycemia with the exception a lower proximal tubular fraction in the female PT-D mice than in the female T-D mice. Further work will focus on the molecular pathways in the females that may confer this kidney protection after the double hit of preterm birth and diabetes. Several sex differences were also identified, including a greater glomerular density in females and lower PT fraction in preterm females. This may be consistent with observation in humans that estrogen may be renoprotective and could affect DKD progression.

Summary of data from male and female cohorts
Data is reported as mean and IQR