Abstract: FR-PO681
Prematurity Reprograms Nephron Progenitor Cells, Impairing Nephrogenesis and Kidney Health
Session Information
- Pediatric Nephrology - 1
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pediatric Nephrology
- 1900 Pediatric Nephrology
Authors
- Amleh, Athar, Hadassah University Medical Center, Jerusalem, Israel
- Piran, Mehran, Monash University, Melbourne, Victoria, Australia
- Moreau, Julie Liliane, Monash University, Melbourne, Victoria, Australia
- Nechama, Morris, Hadassah University Medical Center, Jerusalem, Israel
- Combes, Alexander N., Monash University, Melbourne, Victoria, Australia
- Volovelsky, Oded, Hadassah University Medical Center, Jerusalem, Israel
Background
Premature birth is linked to reduced nephron number and an increased risk of chronic kidney disease. Despite insight from surgical models, the molecular mechanisms by which preterm birth affects nephron formation remain incompletely understood. We aimed to study the changes in nephrogenesis after preterm birth.
Methods
We used a mouse model of induced preterm birth at gestational day 18 using mifepristone, a progesterone antagonist. Nephrons were counted using acid maceration. Kidney function was evaluated via serum sampling and 24-hour urine collection in metabolic cages. Immunofluorescence was used to assess the duration of nephrogenesis (SIX2), nephron progenitor cell (NPC) apoptosis (CASP3), and proliferation (Ki67, BrdU). NPCs were sorted using Six2-GFP and profiled using RNA-sequencing and RT-PCR.
Results
At postnatal day 30, preterm offspring exhibited significantly decreased kidney/body weight ratio and 30% less nephrons alongside elevated serum urea and 24-hour urine albumin levels compared to term counterparts. Notably, the duration of nephrogenesis was extended by one day in preterm kidneys. In preterm kidneys, proliferation was increased in Six2+ NPCs at post-consumption (PC) day 20.5, with no change in apoptosis. Gene expression profiling of NPCs revealed dysregulated Wnt signaling, cell proliferation, hypoxic response, and differentiation signatures in preterm kidneys but not term controls. Preterm NPCs had decreased Six2 but increased Lhx1, Jag1, and Bmp2 expression. Altogether, these results indicate that preterm birth reduces nephron number by altering NPC differentiation and proliferation state.
Conclusion
Preterm birth reduces nephron endowment by altering NPC self-renewal and differentiation dynamics. Therapeutic attempts to boost nephrogenesis after preterm birth may protect against adult kidney morbidity.