Programming of hypertension: the nervous kidney

Abstract

TWO DECADES after Barker and coworkers (2) described an inverse epidemiological relationship between birth weight and risk of adult cardiovascular morbidity, including hypertension, the pathophysiology of prenatally programmed hypertension remains incompletely understood. Experimental models have confirmed that the adult blood pressure profile can be modified by prenatal and early postnatal environment. Prenatal manipulations used to induce hypertension in offspring have included maternal dietary manipulations, maternal glucocorticoid treatment, and reduction of uterine blood flow (18). Work on these models has revealed several factors that may contribute to the pathophysiology, but no unifying concept has emerged from the studies. Instead, competing hypotheses have attributed hypertension to dysfunction of the kidneys, the nervous system, or the peripheral vasculature (18). Although differences between the animal models may result in some variation in experimental observations, it would be surprising if the basic mechanisms were not common to all models. An article by Dagan and coworkers (5a), along with recent work by Ojeda and coworkers (11), is an important step toward reconciling the apparent discrepancy between the roles of the sympathetic nervous system and the kidney.Prenatally programmed hypertension in rat models is salt sensitive (10), consistent with Guyton's kidney-centered hypothesis (6). Following the finding of a low total nephron number in many genetically hypertensive rat strains (4) and in human essential hypertension (7), it was soon reported that rats with prenatally programmed hypertension were also born with reduced nephron endowment (19). However, as discussed by Dagan et al. (5a), later studies have challenged the concept that hypertension is a direct result of decreased glomerular filtration rate and impaired filtration of Na. The authors' own laboratory was able to dissociate both nephron number and glomerular filtration rate from hypertension in the dexamethasone model (12), and Alexander documented an unchanged inulin clearance in the reduced uterine blood flow model (1). Instead, the reported increase in the expression and activity of renal Na transporters supports the hypothesis that inappropriate Na reabsorption along the nephron is key to the initiation of hypertension (5, 9).Proponents of the role of the sympathetic nervous system point to the numerous studies documenting abnormal sympathetic activity in experimental models, suggesting that dysfunctional blood pressure regulation by the sympathetic system is the crucial factor (8,14). Studies in humans have been more ambiguous, but Boguszewski et al. (3), for instance, reported increased sympathetic nerve activity by direct recording from the peroneal nerve in young adults born with a low birth weight.The work by Dagan et al. (5a), employing a rat glucocorticoid-induced model, offers a potential pathogenetic link between the sympathetic nervous system and the kidney. Their results suggest that increased activity of renal nerves,...

Congenital Nephron Deficit and Chronic Kidney Disease

“…Numerous epidemiological studies have shown that adverse prenatal environment and low birth weight are associated with increased risk of hypertension and cardiovascular disease during adulthood [1][2][3]. This "fetal programming" of adult blood pressure profile has been confirmed by multiple experimental studies in animal models [4][5][6]. Although several mechanisms have been postulated to be responsible, most studies have focused on the role of total number of nephrons.…”

“…Even in healthy human populations, there is a wide range in nephron numbers, and the total number has been reported to be low in patients with essential hypertension [7]. In support of a causal role of nephron deficit in the development of hypertension, most experimental models of prenatally programmed hypertension exhibit congenitally low nephron numbers [6,8,9].…”