Placental insufficiency results in temporal alterations in the renin angiotensin system in male hypertensive growth restricted offspring

Abstract

Reduced uterine perfusion initiated in late gestation in the rat results in intrauterine growth restriction (IUGR) and development of hypertension by 4 wk of age. We hypothesize that the renin angiotensin system (RAS), a regulatory system important in the long-term control of blood pressure, may be programmed by placental insufficiency and may contribute to the etiology of IUGR hypertension. We previously reported that RAS blockade abolished hypertension in adult IUGR offspring; however, the mechanisms responsible for the early phase of hypertension are unresolved. Therefore, the purpose of this study was to examine RAS involvement in early programmed hypertension and to determine whether temporal changes in RAS expression are observed in IUGR offspring. Renal renin and angiotensinogen mRNA expression were significantly decreased at birth (80 and 60%, respectively); plasma and renal RAS did not differ in conjunction with hypertension (mean increase of 14 mmHg) in young IUGR offspring; however, hypertension (mean increase of 22 mmHg) in adult IUGR offspring was associated with marked increases in renal angiotensin-converting enzyme (ACE) activity (122%) and renal renin and angiotensinogen mRNA (7-fold and 7.4-fold, respectively), but no change in renal ANG II or angiotensin type 1 receptor. ACE inhibition (enalapril, 10 mg x kg(-1) x day(-1), administered from 2 to 4 wk of age) abolished hypertension in IUGR at 4 wk of age (decrease of 15 mmHg, respectively) with no significant depressor effect in control offspring. Therefore, temporal alterations in renal RAS are observed in IUGR offspring and may play a key role in the etiology of IUGR hypertension.

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

“…There was a trend for increased total protein levels in sham rats treated with 5 mg/kg per day ELP‐VEGF, but it is possible that degradation products of the infused protein itself are being detected in this assay. It has been widely studied that the RUPP surgery induces fetal resorption and intrauterine growth restriction of the surviving pups 72, 73, 74, 75, 76. Fetal resorption and fetal growth restriction was observed in our study as well (Table 1 and Figure S3), validating the success of the RUPP procedure in our rats.…”

The Clinical Importance of Nephron Mass

“…123 In a larger study of 19-year-olds who were very preterm, stratified by weight for gestational age, birth weight correlated negatively with serum creatinine and albuminuria and positively with GFR. 124 These results are consistent with those of others, but as has been shown in animal studies, pro- Renal dysfunction Increased renal vascular reactivity 1renal artery response to ␤-adrenergic stimuli and sensitivity to adenylyl cyclase in growth-restricted rats 184,186,187 Altered vascular reactivity 2flow-mediated dilation in LBW children 107,[188][189][190] 1uric acid Endothelial dysfunction Impaired vascular structure and capillary density Altered RAS Administration of inhibitors of RAS abrogates later hypertension 4,30,111,177,191 Administration of angiotensin II causes increased hypertensive response Evidence of expression of AT1R and AT2R and ACE activity are divergent at different stages and in different models of programming Overall, programmed suppression of intrarenal RAS during nephrogenesis and postnatal upregulation of AT1R are most consistent Altered sodium handling 2fractional excretion of sodium 22,109,110,174,192 1expression of BSC1 and TSC 1expression of glucocorticoid receptor 1expression of glucocorticoid responsive ␣1 and ␤1 subunits of Na/K-ATPase 1expression of NHE3 1expression of ␤ and ␥ ENaC Increased sympathetic nervous system activity Renal denervation reduced systolic BP and sodium transporter expression 193 Catch-up growth/obesity Higher BP in children who catch up fastest 98,154 Reduced flow-mediated dilation with higher rate of weight gain AT1R, angiotensin subtype 1 receptor; AT2R, angiotensin subtype 2 receptor; BSC1, bumetanide-sensitive co-transporter; ENaC, epithelial sodium channel; NHE3, sodium hydrogen exchanger; RAS, renin-angiotensin system; TSC, thiazide-sensitive co-transporter.…”

Fetal and Infant Growth Patterns and Kidney Function at School Age

“…Experimental studies showed alterations in the renin angiotensin system in experimentally induced intrauterine growth-restricted individuals at adult age, and these differences were not present at younger age. 32 Several markers of the renin angiotensin system were increased in intrauterine growth-restricted subjects with hypertension. 32 Future studies are needed to identify possible Figure 2.…”

“…32 Several markers of the renin angiotensin system were increased in intrauterine growth-restricted subjects with hypertension. 32 Future studies are needed to identify possible Figure 2. Associations of birth outcomes with kidney outcomes (n=6482).…”