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Am J Physiol Renal Physiol 295: F27-F28, 2008. First published May 7, 2008; doi:10.1152/ajprenal.90270.2008
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EDITORIAL FOCUS

Programming of hypertension: the nervous kidney

V. Matti Vehaskari

The Research Institute for Children and Louisiana State University Health Sciences Center, New Orleans, New Orleans, Louisiana

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, independently of the rest of the peripheral nervous system, may be the trigger for the initiation of volume expansion and hypertension. Renal sympathetic activity (measured as whole kidney norepinephrine content) was increased in the prehypertensive stage, and renal denervation prevented not only the development of hypertension but also the rise in the expression of those specific renal Na transporters that were to become upregulated during the development of hypertension. Renal denervation had no effect on control animals. The findings support the conclusion that the intervention disrupted the specific sympathetic nerve-mediated pathophysiological cascade leading to increased Na reabsorption and hypertension.

The mechanism by which renal denervation aborts the upregulation of Na transporters and the development of hypertension awaits further study. Dagan et al. (5a) propose that denervation prevented direct activation of Na transport in the proximal tubule, the thick ascending limb, and the distal convoluted tubule by sympathetic fibers, but other, not mutually exclusive, possibilities exist. The prehypertensive stage has been shown to be associated with an altered tubulointerstitial microenvironment, including immune cell infiltration and increased oxidative stress (16), both of which are known to stimulate Na reabsorption (15). Causality is suggested by the fact that pharmacological blockade of inflammation and oxidative stress prevents the development of hypertension (16). 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 renin-angiotensin system, which has been proposed to play a role in the pathogenesis (17).

The cause of increased renal sympathetic activity is unknown, but it is likely that it is part of a generalized increase in sympathetic outflow (even though the renal innervation seems critical to the development of hypertension). A known (transient) cause of increased sympathetic activity is response to stress and some experimental (8) and human studies (13) have suggested that prenatal conditions may program heightened postnatal stress reactivity. For instance, in a recent report subjects born with a small birth weight after the Dutch famine exhibited an enhanced hemodynamic response to psychological stress as adults (13). One could speculate that the first stage in the pathogenesis is intermittently increased renal sympathetic stimulation, which may then lead to cumulative tubulointerstitial injury and Na retention.

It is important to emphasize that the focus of the study by Dagan et al. (5a) and this commentary is only on the initial development phase of prenatally programmed hypertension. As in many other models, once hypertension is established, it may become sustained independently of the initiating mechanisms. Consistent with this view, Dagan et al. (5a) did not find differences in renal norepinephrine content during a later stage, and we have previously reported a return of renal Na transporter levels toward the baseline despite persisting hypertension (9). It should also be noted that many of the mechanisms discussed above may apply to common essential hypertension, and one might argue that prenatally programmed hypertension is just a special example of essential hypertension.


   FOOTNOTES
 

Address for reprint requests and other correspondence: V. M. Vehaskari, The Research Institute for Children and Louisiana State University Health Sciences Center, New Orleans, 200 Henry Clay Ave., New Orleans, LA 70118 (e-mail: vvehas{at}lsuhsc.edu)


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This Article
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295/1/F27    most recent
90270.2008v1
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