Preterm Birth Increases Susceptibility to Hyperglycemia-Induced Kidney Injury With Sex-Specific Differences in...

Area of Science:

• Nephrology
• Endocrinology
• Developmental Biology

Background:

• Preterm birth is a known risk factor for diabetes and chronic kidney disease (CKD).
• The specific impact of preterm birth on the development and progression of diabetic kidney disease (DKD) remains unclear.
• Previous studies indicated male preterm mice with diabetes exhibit early DKD features, including reduced podocyte density and altered gene expression.

Purpose of the Study:

• To investigate whether preterm birth accelerates DKD progression in female mice.
• To compare structural and transcriptomic outcomes in female mice to a prior cohort of male mice to identify sex-specific differences in DKD.
• To understand the long-term renal consequences of preterm birth in the context of diabetes.

Main Methods:

• Female mice were delivered preterm (19 days post conception) or at term (20 days post conception).
• Hyperglycemia was induced using streptozotocin to create term-diabetic (T-D) and preterm-diabetic (PT-D) groups.
• Kidney tissues were analyzed using histological, stereological, imaging, and transcriptomic methods at 18 weeks.

Main Results:

• Preterm-diabetic (PT-D) females exhibited higher albuminuria, reduced proximal tubule (PT) fraction, and pro-fibrotic gene activation compared to term-nondiabetic (T-ND) females.
• PT-D females showed increased blood urea nitrogen (BUN) and a lower PT fraction than T-D females, linked to vascular pathway activation and suppressed mitochondrial metabolism.
• Sex differences included a lower PT fraction and fewer atubular glomeruli in PT-D females versus males; renin expression decreased in PT-D males but not females. Notch signaling was upregulated in both sexes.

Conclusions:

• Preterm birth sensitizes female kidneys to injury following hyperglycemia exposure.
• Despite increased susceptibility, preterm females with hyperglycemia demonstrate relative resistance to kidney damage compared to males.
• The findings reveal significant sex-specific variations in DKD progression influenced by preterm birth and hyperglycemia.