Intrauterine Growth Restriction Programs Greater Susceptibility to Chronic Kidney Injury in Male and Female Aged Rats
Authors: Newsome Ashley D. , Davis Gwendolyn K. , Alexander Barbara T. 
Published: November 2023

Although the correlation between low birth weight (LBW) and increased risk of chronic kidney disease (CKD) is well‐established, the mechanisms involved remain unknown. Our laboratory uses a rodent model of intrauterine growth restriction (IUGR) to study the etiology of the developmental programming of enhanced cardio‐renal risk. Previous studies by our laboratory report that blood pressure (BP) is increased in male IUGR offspring relative to male controls at 4 months of age whereas female IUGR remain normotensive. However, BP is elevated by 12 months of age in female IUGR indicating that female IUGR do not remain protected. Male IUGR exhibit an enhanced susceptibility to acute renal injury at 4 months of age, but whether female IUGR exhibit a similar response is unknown. Epidemiological data related to sex differences in this phenomenon are limited, especially with regard to the effect of aging, but suggest that males progress to renal failure more rapidly than females. Thus, this study tested the hypothesis that IUGR offspring exhibit a sex difference in enhanced susceptibility to a chronic renal insult in later life. At 16 ± 1 months of age, control and IUGR rats underwent sham or uni‐nephrectomy (UNI‐X) to reduce renal mass. 24‐hour metabolic studies were performed before and one‐month post‐surgery to compare urinary markers of kidney injury. After one month of recovery, rats underwent carotid and jugular catheterization with BP and glomerular filtration rate (GFR) measured in conscious rats. Measurement of GFR involved the transcutaneous clearance method using intravenous injection of FITC‐sinistrin. Data were analyzed by 2‐way ANOVA with Tukey's multiple comparisons post‐test. After one month of reduced renal mass, GFR was not altered in male and female controls (Table). However, GFR was significantly reduced in male and female UNI‐X IUGR relative to their same‐sex sham counterparts (Table). Although UNI‐X reduced GFR by 43% in male IUGR compared to a 28% reduction in female IUGR relative to same‐sex shams, this difference was not statistically significant. BP was not significantly altered post‐UNI‐X in any groups (data not shown). Renal cortical expression of TNF‐α and TGF‐β were significantly elevated by 9‐fold and 3‐fold (P<0.05), respectively, in male UNI‐X IUGR compared to male sham IUGR and male control groups. This suggests that an exacerbated increase in renal inflammation in response to UNI‐X may be a contributory factor to enhanced susceptibility to chronic renal injury in male IUGR. Whether female UNI‐X IUGR exhibit a similar increase is not yet known. Therefore, these data suggest that both male and female IUGR demonstrate a greater susceptibility to chronic renal injury in later life than normal birthweight controls. Furthermore, this study indicates that optimization of treatments to improve the health of renal patients should involve a complete patient perinatal history and that investing in further efforts to understand the link between the in utero environment and adult health is invaluable.Support or Funding InformationNIH: F30DK112718‐01, T32HL105324‐07, HL074927, HL51971, P20GM104357; AHA: GRNT19900004.

GFR (mL/min/100 g body weight)
Male
Female

Control Sham
0.78 ± 0.06
0.89 ± 0.08

Control UNI‐X
0.54 ± 0.07
0.77 ± 0.03

IUGR Sham
0.71 ± 0.09
0.98 ± 0.07

IUGR UNI‐X
0.40 ± 0.10*
0.70 ± 0.02*

P<0.05 vs Same‐Sex Sham.