Renal and extrarenal mechanisms of perinatal programming after intrauterine growth restriction

Abstract

The concept of fetal programming of disease in later life after intrauterine growth restriction (IUGR) has opened a potential new perspective on the treatment and prevention of arterial hypertension. Numerous large studies have recently confirmed the relationship between low birth weight and raised blood pressure. Hyperalimentation after birth appears to add to the risk of higher blood pressure later in life. However, there is still a controversy and clear intervention studies have not yet been possible. Therefore, the gain of knowledge about the underlying mechanisms of fetal programming is of utmost importance.Two major groups of mechanisms may be identified: renal and extrarenal mechanisms. Renal mechanisms include the reduction of nephron number, which is encountered in patients and animals with low birth weight. According to the so-called Brenner hypothesis, this may lead to increased arterial blood pressure. Another important renal system is the renin-angiotensin-aldosterone system, which appears to be more active on a number of levels in low birth weight individuals. Finally, there is the conversion of cortisol to inactive cortisone by the 11b-hydroxysteroid dehydrogenase in distal tubule cells, which is reduced after intrauterine growth restriction. This enables a more powerful activation of mineralocorticoid receptors by cortisol. Extrarenal mechanisms include alterations in vascular structure (primary and secondary), increased activity of the sympathetic nerve system, and maybe most interestingly, an impairment of endothelial function. The latter is at least partially caused by an inactivation of nitric oxide by an excess of free oxygen radicals. In summary, mechanisms of fetal programming are only in the process of being revealed, and research has to focus on finding the key mechanism that might allow for successful intervention.

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.…”

Associations of Infant Feeding and Timing of Weight Gain and Linear Growth during Early Life with Childhood Blood Pressure: Findings from a Prospective Population Based Cohort Study

“…[2] Fetal growth restriction has been identified as a risk factor for raised BP in later life. [3,4] Studies addressing the relationship of weight gain in infancy to later life BP have shown mixed results. The Helsinki Birth Cohort study showed an inverse association between infant weight gain and later life BP.…”

Segmental sodium reabsorption by the renal tubule in prenatally programmed hypertension in the rat

“…However, programmed nephron deficit has also been described in the absence of hypertension [8], which has led to the suggestion that concomitant changes in renal function must occur in order for hypertension to develop [9]. A major candidate is the intrarenal renin-angiotensin system, which displays altered activity in several models of developmental programming [10,11]. However, there are other changes in the kidney that may also contribute to the onset of hypertension, most notable of which is an increase in renal tubular sodium transporter expression.…”