Evaluation of kidney dysfunction and angiotensinogen as an early novel biomarker of intrauterine growth restricted offspring rats

Abstract

Background: Few studies have addressed the growing concerns of chronic kidney diseases in children with intrauterine growth restriction (IUGR). Therefore, the purpose of this study was to evaluate long-term kidney dysfunction and determine if urinary angiotensinogen (AGT) was suitable as a novel early biomarker for kidney dysfunction in IUGR offspring. Methods: Pregnant rats underwent bilateral uterine artery ligation, and as a control group, sham surgeries were performed. results: The birth weight was reduced, the urinary AGT to creatinine ratio was significantly higher at week 20, and urinary protein levels were significantly higher at week 32 in IUGR rats than in control rats. On the other hand, the histological findings at week 32 revealed long-term kidney dysfunction, more severe glomerulosclerosis, and greater glomerular diameters in IUGR rats. Moreover, AGT mRNA expression and immunohistological staining were significantly increased in IUGR rats; this suggests that the intrarenal renin-angiotensin system (RAS) contributes to renal dysfunction of IUGR offspring. conclusion: Urinary AGT elevation prior to urinary protein levels suggests that AGT is an early biomarker. At week 32, kidney dysfunction was severe in IUGR rats and intrarenal RAS appeared to be one of the causes. (1) first proposed that many adult diseases may have origins in fetal life, subsequent studies have clarified the associations between intrauterine growth restriction (IUGR) and obesity, hypertension, insulin resistance, and coronary artery disease. Luyckx and Brenner (2) applied these findings to the development of chronic kidney disease and following studies were conducted in animal models as well as human subjects. In these animal studies, IUGR was typically found to be induced by maternal food restriction (3-5); however, no applications to current IUGR rates in developed countries were made; malnutrition during pregnancy due to food restriction during pregnancy is no longer the main cause of IUGR in developed countries.Most cases of IUGR reportedly result from decreased placenta blood flow (6). A decrease in placenta blood flow by maternal bilateral uterine artery ligation was shown in an animal model; however, relatively few studies have been conducted to evaluate subsequent kidney dysfunction. To the best of our knowledge, no previous study has assessed the long-term effects of IUGR on kidney function. Therefore, in this study, we examined kidney dysfunction in a rat model of IUGR induced by bilateral uterine artery ligation for 32 wk after birth.On conducting this study, we also decided to identify clues to detect dormant chronic kidney disease in adults who were born with a low birth weight. Owing to developments in the field of neonatology, the survival rate of infants with a low birth weight has continued to increase (7). Although the first generation of infants from the "surfactant era" who may have chronic kidney disease pathogenesis are now reaching young adulthood, no reliable screening methods or followup procedures to mon...

Transient enalapril attenuates the reduction in glomerular filtration rate in prenatally programmed rats

“…; Murano et al. ). We have recently shown that transient administration of enalapril administered between 21 and 42 days of age and continuous administration of enalapril normalized the elevated urinary angiotensinogen and urinary angiotensin II (indirect markers of the intrarenal renin angiotensin II system (Kobori et al.…”

Transient Exposure of Enalapril Normalizes Prenatal Programming of Hypertension and Urinary Angiotensinogen Excretion

“…Interestingly a study examined the effect of prenatal programming using a model of uterine artery ligation. At 32 weeks of age, programmed rats had no difference in plasma angiotensinogen compared to control rats, while, compared to controls, the programmed rats had significantly higher urinary angiotensinogen/creatinine levels at 20 and 32 weeks of age [ 45 ]. These findings are in concordance with our findings showing that prenatal programming has no effect on plasma angiotensinogen levels but causes a marked increase in urinary excretion of angiotensinogen.…”

Long‐term renal tubular damage in intrauterine growth‐restricted rats

“…In previous studies of kidney dysfunction with IUGR, glomerular dysfunction has mainly been reported, and relatively few studies have been carried out on subsequent renal tubular dysfunction.…”

“…Brenner and Chertow suggested that the reduced number of glomeruli leads to hyperfiltration, which subsequently leads to systemic hypertension, glomerular sclerosis, and progressive deterioration of renal function . Our previous study also reported dilated diameter and sclerosis of glomeruli in IUGR rats . Including that study, however, most studies have focused on glomerular function, and limited information is available linking IUGR with renal tubular damage.…”

“…9 Our previous study also reported dilated diameter and sclerosis of glomeruli in IUGR rats. 10 Including that study, however, most studies have focused on glomerular function, and limited information is available linking IUGR with renal tubular damage. Although glomeruli play an important role in filtration, the renal tubules play an important role in reabsorption.…”