Preterm Birth Increases Susceptibility to Hyperglycemia‐Induced Kidney Injury With Sex‐Specific Differences in Structural and Molecular Responses

BACKGROUND: Preterm birth increases the long-term risk of diabetes and chronic kidney disease (CKD), yet its impact on diabetic kidney disease (DKD) is unclear. We previously showed that male preterm mice with diabetes develop early features of DKD, including reduced podocyte density, decreased renin expression, activation of angiogenesis pathways, and impaired endothelial-podocyte signaling. Here, we examine whether preterm birth similarly accelerates DKD progression in female mice and compare structural and transcriptomic outcomes in the females to the prior male cohort to assess sex-specific differences. METHODS: Preterm mice were delivered by Caesarean section at 19 days post conception (dpc) and term mice at 20 dpc. Hyperglycemia was induced at 6 weeks with streptozotocin to generate term-diabetic (T-D) and preterm-diabetic (PT-D) groups; controls were term-nondiabetic (T-ND) and preterm-nondiabetic (PT-ND). Body weight and glucose were monitored, and kidneys were analyzed at 18 weeks using histologic, stereologic, imaging, and transcriptomic methods. RESULTS: Compared with T-ND females, PT-D females showed higher albuminuria, more atubular glomeruli, reduced proximal tubule (PT) fraction, and pro-fibrotic gene activation. Compared to T-D females, PT-D females had higher blood urea nitrogen (BUN) levels and reduced PT fraction. This was associated with activation of pathways associated with the vasculature and suppression of mitochondrial metabolism gene pathways, along with Notch signalling alterations. Sex differences included a lower PT fraction in preterm females than males and fewer atubular glomeruli in PT-D females than PT-D males. Renin expression was lower in PT-D than T-D in males only. When comparing PT-D to T-D across sexes, 582 differentially expressed genes were unique to females. Notch signalling was upregulated in both male and female PT-D mice compared to T-D. CONCLUSION: Preterm birth increases susceptibility to kidney injury in females after exposure to hyperglycemia. However, preterm females with hyperglycemia are more resistant to kidney damage than males.