Kidney angiotensin and angiotensin receptor expression in prenatally programmed hypertension

Abstract

Manning. Kidney angiotensin and angiotensin receptor expression in prenatally programmed hypertension. Am J Physiol Renal Physiol 287: F262-F267, 2004. First published April 20, 2004 10.1152/ajprenal.00055.2004.-Adult hypertension may be programmed by the prenatal environment in humans and in experimental animals. The potential role of the intrarenal renin-angiotensin system (RAS) in prenatally programmed hypertension was investigated. Hypertension in rat offspring was induced by maternal protein restriction during pregnancy. The offspring were studied on day 1 of life and immediately preceding the development of hypertension on day 28. ANG I and II contents were determined by radioimmunoassy. Angiotensin receptor protein and mRNA levels were quantified by immunoblotting and real-time RT-PCR, respectively. Plasma and kidney ANG I and II were unchanged in the offspring from low-protein pregnancies (LP). ANG II type 1 receptor (AT1R) protein abundance was low in the newborn LP kidney (P Ͻ 0.05) but rose above control values by 28 days of age (P Ͻ 0.05); the rise was associated with an increase in AT1R subtype A (P Ͻ 0.01), but not subtype B, mRNA level. ANG II type 2 receptor protein expression was decreased on day 1 (P Ͻ 0.05) and increased on day 28 (P Ͻ 0.05) in LP kidneys. The results show that prenatal programming of hypertension is associated with an abnormal pattern of intrarenal RAS ontogeny that may play a pathogenetic role, for instance, by constitutively altering renal hemodynamics or Na reabsorption.fetal origins of adult disease; kidney ontogeny; low-protein diet THE CONCEPT OF "PRENATAL PROGRAMMING of adult disease" refers to modulation of future adult phenotype by nongenetic environmental factors in utero. Programming of hypertension is the most extensively studied example of prenatal programming. Both epidemiological data (2,7,8,19,24) and experimental studies (18,22,36,39) have provided strong evidence that prenatal environment can modify adult blood pressure. The development of hypertension has been linked to intrauterine growth retardation in humans (1,2,7,8,19,24) and rats (18,22,36,39), suggesting a common mechanism despite species differences. In experimental animals, maternal protein (18,36,39) and calorie (38) restriction and maternal dexamethasone treatment (9, 29) have been used to program adult hypertension in offspring.The mechanisms of the development of hypertension in offspring are unclear. Although other mechanisms such as a disordered hypothalamic-pituitary-adrenal axis have been proposed (34), there is strong evidence to support a role for the kidney in the pathogenesis. Several studies have documented a deficit in the total number of nephrons in experimental programming of hypertension (17,36,39). A recent study of humans with essential hypertension also reported a decrease in the nephron count (15), consistent with the hypothesis that congenital nephron deficit has a role in essential hypertension (4). On the other hand, we reported upregulation in renal sodium (Na) transporter...

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.…”

Prenatal Programming of Hypertension

“…In our longitudinal study, we observed a switch from low to high plasma renin activity in the rat, but the switch occurred only after hypertension was established (14). Plasma angiotensin I and II concentrations were unchanged during the prehypertensive stage (97). These results cast doubt on the role of circulating hyperreninemia in the pathogenesis of the hypertension.…”

“…Accumulating evidence suggests that activation of the RAS within the kidney, independent of the state of the systemic RAS, may induce Na retention and sustained hypertension (113). Despite that the intrarenal RAS is suppressed in the neonatal period in prenatally programmed hypertension in the rat, AT1R expression increases above control levels during the prehypertensive stage (97,114), without feedback suppression in kidney angiotensin I or II contents (97). In sheep that have been programmed to become hypertensive by maternal glucocorticoid treatment (115) or by maternal food restriction (70), upregulation of renal AT1R has been documented already in late gestation and at birth, respectively, perhaps reflecting the much more advanced maturation state of the ovine kidney.…”

Programming of hypertension: the nervous kidney

“…Because ischemia is a powerful inducer of reactive oxygen species production, vasoconstriction and ischemia due to sympathetic activity is a possible contributor to tubulointerstitial oxidative stress. In addition, sympathetic activity may stimulate Na transport through activation of the intrarenal reninangiotensin system, which has been proposed to play a role in the pathogenesis (17).…”