Date Published: March 7, 2019
Publisher: Public Library of Science
Author(s): Ashley D. Newsome, Gwendolyn K. Davis, Osasu N. Adah, Norma B. Ojeda, Barbara T. Alexander, Jaap A. Joles.
Epidemiological studies report an inverse association between birth weight and risk for kidney disease that may differ between males and females, but studies investigating this association are limited. This study tested the hypothesis that male intrauterine growth-restricted offspring in a model of low birth weight induced by placental insufficiency in the rat exhibit enhanced renal injury in response to a persistent secondary renal insult while female growth-restricted offspring are protected. For this study, control offspring from sham-operated dams and growth-restricted offspring from reduced uterine perfusion dams underwent uninephrectomy or a sham procedure at 18 months of age. One month later, urinary markers of renal injury, renal function, and histological damage were measured. Results were analyzed using 2-way ANOVA. Male and female offspring were assessed separately. Proteinuria and urinary neutrophil gelatinase-associated lipocalin were significantly elevated in male growth-restricted offspring exposed to uninephrectomy when compared to male uninephrectomized control. Urinary kidney injury marker-1 was elevated in male uninephrectomized growth-restricted offspring relative to male sham growth-restricted but not to male uninephrectomized controls. Likewise, urinary neutrophil gelatinase-associated lipocalin was elevated in female uninephrectomized growth-restricted offspring but only when compared to female sham growth-restricted offspring. Markers of renal function including glomerular filtration rate and serum creatinine were impaired after uninephrectomy in female offspring regardless of birth weight. Histological parameters did not differ between control and growth-restricted offspring. Collectively, these studies suggest that both male and female growth-restricted offspring demonstrate susceptibility to renal injury following uninephrectomy; however, only male growth-restricted offspring exhibited an increase in renal markers of injury in response to uninephrectomy relative to same-sex control counterparts. These findings further suggest that urinary excretion of protein, kidney injury marker-1, and neutrophil gelatinase-associated lipocalin may be early markers of kidney injury in growth-restricted offspring exposed to a secondary renal insult such as reduction in renal mass.
Low birth weight (LBW), defined as less than 2500 grams in humans, is a well-established risk factor for hypertension [1–5], impaired glucose homeostasis [1, 6–10], and reduced nephron number [11,12]. Epidemiological studies also report that LBW individuals are more likely to develop chronic kidney disease (CKD) and end-stage renal disease [13–18]. Although the increased prevalence of hypertension and diabetes among LBW individuals contributes to this association, evidence suggests that these factors alone do not fully account for the greater risk of kidney disease [15, 19–20]. Several studies indicate that CKD risk may differ between LBW men and LBW women [20, 21]. Experimental studies also report that the age-related decline in renal function and injury differs between male and female offspring exposed to a developmental insult [22–27]. Likewise, numerous experimental models of LBW or intrauterine growth restriction (IUGR) report that male growth-restricted offspring exhibit elevated blood pressure during early adulthood while female littermates are protected [27–35]. Collectively, these studies demonstrate that adverse events during early life program enhanced risk for later chronic disease that may differ by sex. Yet, whether LBW or IUGR programs an enhanced vulnerability to a secondary renal insult in adulthood is not well defined. Additionally, whether the renal response to an additional renal insult in later life differs in males and females is also understudied.
Timed pregnant primigravid Sprague-Dawley dams (Envigo, Madison, WI) at 10–12 weeks of age were received on day 13 of gestation and housed individually in a temperature-controlled room at 23°C with a 12:12 hour light/dark cycle. They were fed a global soy protein-free extruded rodent diet (Envigo) to avoid the effect of dietary phytoestrogens and were given water ad libitum. All procedures were done in compliance with the National Institutes of Health guidelines for use and care of animals, and the protocol was approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center (Protocol Number: 0878E). All surgeries were performed under isoflurane anesthesia with carprofen provided for post-surgical pain control, and all efforts were made to minimize suffering. A total of 12 sham-operated and 14 reduced uterine perfusion pressure dams were used to generate all offspring utilized in the following study.
The results of this study indicate that male growth-restricted offspring exposed to uninephrectomy in later life had a significant increase in proteinuria and urinary excretion of NGAL compared to uninephrectomized male controls and sham-operated male growth-restricted counterparts. In addition, male growth-restricted offspring who underwent uninephrectomy had increased KIM-1 compared to sham-operated male growth-restricted offspring. NGAL was also significantly increased in female growth-restricted offspring exposed to uninephrectomy relative to sham-operated growth-restricted females, but exhibited no differences in urinary KIM-1 or proteinuria. Together, these results suggest that growth-restricted offspring and male growth-restricted offspring in particular, are more susceptible to a persistent renal insult such as uninephrectomy in later life. Measures of renal function and markers of histological renal injury did not differ after uninephrectomy between same-sex control and growth-restricted offspring. Therefore, these data suggest that urinary markers may serve as early biomarkers of renal injury before functional or histological changes occur in offspring exposed to intrauterine growth restriction.