95 - Gene dysregulation in the kidney of a murine model of preterm birth may provide a link between low nephron number and sodium regulation
Friday, April 22, 2022
6:15 PM – 8:45 PM US MT
Poster Number: 95 Publication Number: 95.138
Evan Rajadhyaksha, University of Virginia School of Medicine, Charlottesville, VA, United States; Aleksandra Cwiek, University of Virginia, Charlottesville, VA, United States; Kimberly deRonde, University of Virginia School of Medicine, Charlottesville, VA, United States; Kevin M. Bennett, Washington University in St. Louis, St. Louis, MO, United States; Masako Suzuki, ALBERT EINSTEIN COLLEGE OF MEDICINE, INC, Bronx, NY, United States; Kimberly J. Reidy, Albert Einstein College of Medicine, Children's Hospital at Montefiore, Bronx, NY, United States; Jennifer R. Charlton, University of Virginia School of Medicine, Charlottesville, VA, United States
Resident University of Virginia Department of Pediatrics Charlottesville, Virginia, United States
Background: Preterm birth is a significant risk factor for the development of hypertension (HTN) and chronic kidney disease (CKD). We previously demonstrated that mice born 2 days prior to full term gestation exhibit gene dysregulation in the kidney just after birth. Pathways involved included angiogenesis, fat soluble vitamin metabolism, renin-angiotensin, and the proximal tubule. Additionally, the nephron progenitor cells of preterm mice underwent premature differentiation, conferring a shortened window of nephrogenesis.
Objective: To understand the molecular, histologic, and functional changes in the kidneys of adult mice born preterm. We hypothesized that the kidneys of adult mice born preterm would have altered gene expression, concurrent with evidence of CKD.
Design/Methods: Timed-pregnant CD-1 dams were assigned to a preterm (C-section at 18 days post conception (dpc), n=16) or term (20 dpc, n=29) group. At six weeks, glomerular filtration rate (GFR) was measured transdermally followed by administration of cationic ferritin (CF) to measure glomerular number by CF-enhanced MRI. Gene expression profiles of the whole kidney were analyzed by RNA-Seq, accounting for sex as a covariate. Significance was determined by false discovery rate adjusted p< 0.05 and absolute log2 (fold-change) >1. Kidneys were evaluated by histology to identify pathology and count atubular glomeruli (ATG).
Results: The preterm and term groups had similar kidney and body weights, but the preterm group had a higher kidney weight normalized to body weight. The preterm group had 14% fewer glomeruli with no difference in GFR (Table). There were no histopathological alterations in the preterm group and no difference in the number of ATG between the groups. Bulk RNA-Seq of the kidney identified 25 differentially expressed genes, with increased expression of Slc12a3 and decreased expression of Gsta2, Tshz3, and Bco2 in the premature group compared to the term group, independent of sex.Conclusion(s): This is the first study to identify a potential mechanism for increased sodium reabsorption in a model of preterm birth. We observed upregulation of the Slc12a3 gene, which encodes for the sodium-chloride cotransporter in the distal convoluted tubule, in the preterm group. This parallels observations in mouse models of diabetes and genetic models of reduced nephron endowment. We also observed dysregulation of several other genes of interest, but no measurable functional changes. Further investigation is needed to determine if any of these gene changes represent a targetable therapeutic option for patients born preterm and at risk for HTN and CKD. CV_Evan RajadhyakshaEvan_CV January 2022.pdf