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(Hypertension. 1998;32:376-377.)
© 1998 American Heart Association, Inc.

Letters to the Editor

Leptin and the Renin-Angiotensin-Aldosterone System

Stefan R. Bornstein; ; David J. Torpy

National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md

To the Editor:

Shek et al¹ recently reported in a very detailed study that chronic leptin infusion in rats increased mean arterial blood pressure. However, the mechanism of leptin-induced hypertension is unclear and may involve both central and peripheral actions. While the sympathoexcitatory action of leptin is well established and may be a major factor mediating its hypertensive effect,^{1 2} the role of leptin in another major regulator of blood pressure, the renin-angiotensin-aldosterone system, has yet to be defined. Shek et al provide the first data on renin and aldosterone levels after leptin treatment in vivo.¹ Whereas renin levels were unchanged, aldosterone tended to decrease at higher doses. In accordance with these findings, previous studies have shown that infusion of leptin caused natriuresis and diuresis.³ The authors suggest that reduced plasma aldosterone levels may be due to reduced potassium intake associated with leptin-induced anorexia. We suggest that a more likely explanation is a direct effect of leptin on the adrenal cortex. We have previously demonstrated in primary adrenal cell cultures that leptin can directly inhibit adrenocortical steroid production and the mRNA expression of cytochrome P450 enzymes.⁴ Therefore, leptin can chronically depress steroid production at the level of the adrenal, which is in line with the in vivo data reported in this study. In addition, our preliminary data demonstrate a slight increase in plasma renin activity in rats chronically treated with leptin (0.12 mg/kg per day IP over 7 days). In treated animals, we observed a trend toward increased plasma renin activity (leptin-treated, 9.3±1.0 (n=7); vehicle-treated, 6.9±0.60; P=0.15). The renin increase may have been due to increased sympathetic activity. The results of our study and those of Shek et al suggest that leptin may influence the mineralocorticoid axis and perhaps participate in the hypertension observed with human obesity.

In addition, the hyperleptinemia that occurs in critically ill patients⁵ may contribute to the hyperreninemic hypoaldosteronism that is found in a substantial percentage of these patients.⁶ The effects of leptin on the mineralocorticoid axis in humans need to be studied directly.

References

1. Shek EW, Brands MW, Hall JE. Chronic leptin infusion increases arterial pressure. Hypertension. 1998;31(pt 2):409–414.

2. Haynes WG, Sivitz WI, Morgan DA, Walsh SA, Mark AL. Sympathetic and cardiorenal actions of leptin. Hypertension. 1997;30(pt 2):619–623.

3. Jackson EK, Li P. Human leptin has natriuretic activity in the rat. Am J Physiol. 1997;272(pt 2):F333–F338.

4. Bornstein SR, Uhlmann K, Haidan A, Ehrhart-Bornstein M, Scherbaum WA. Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. Diabetes. 1997;46:1235–1238.[Abstract]

5. Bornstein SR, Licinio J, Tauchnitz R, Engelmann L, Negrao AB, Gold P, Chrousos GP. Plasma leptin levels are increased in survivors of acute sepsis: associated loss of diurnal rhythm in cortisol and leptin secretion. J Clin Endocrinol Metab. 1998;83:280–283.[Abstract/Free Full Text]

6. Zipser RD, Davenport MW, Martin KL, Tuck ML, Warner NE, Swinney RR, Davis CL, Horton R. Hyperreninemic hypoaldosteronism in the critically ill: a new study. J Clin Endocrinol Metab. 1981;53:867–873.[Abstract/Free Full Text]

Response

Eugene W. Shek; Michael W. Brands; ; John E. Hall

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Miss

We appreciate the interest of Drs Bornstein and Torpy in our recent study which demonstrated that chronic elevation of plasma leptin concentration, to levels similar to those found in obesity, increased mean arterial pressure in rats.¹ Drs Bornstein and Torpy raised two issues in their letter. (1) They suggested that the slight reductions in plasma aldosterone measured in our studies might be due to a direct inhibitory effect of leptin on the adrenal glomerulosa cells, and (2) they proposed that "leptin may influence the mineralocorticoid axis and perhaps participate in the hypertension observed with human obesity."

On the basis of their novel observation that leptin inhibits adrenocortical cortisol production,² Drs Bornstein and Torpy suggest that a direct effect of leptin on the adrenal gland may explain the decreased plasma aldosterone and corticosterone concentrations observed during chronic leptin infusion in our studies. However, it is important to note that Bornstein and Torpy studied the acute effects of leptin on cortisol secretion rather than aldosterone or corticosterone. Aldosterone and corticosterone secretion often do not change in parallel with cortisol. For example, potassium, one of the most powerful regulators of aldosterone and corticosterone secretion, has little effect on cortisol secretion. We are not aware of any evidence that leptin chronically reduces aldosterone secretion via a direct effect on the adrenal gland. In fact, recent studies by Malendowicz et al³ suggest that leptin may directly increase aldosterone and corticosterone production by rat zona glomerulosa cells. Thus, it is questionable whether a direct effect of leptin on the adrenal glands could account for the decrease in plasma aldosterone concentration observed in our studies. On the other hand, there is substantial support for our suggestion that decreased potassium intake, associated with the effect of leptin to reduce food intake, could account for a chronic reduction in aldosterone secretion. Many previous studies indicate that reducing potassium intake significantly decreases mineralocorticoid secretion.⁴ In our experiments, food intake (and therefore potassium intake, since all of the daily intake of potassium was provided in the food) was reduced by 65% to 70% at the higher rate of leptin infusion, which also decreased plasma aldosterone and corticosterone concentrations by 30% to 50%. However, direct testing of this possibility would require studies in which potassium intake was maintained constant during chronic leptin infusion.

With regard to the second point raised by Drs Bornstein and Torpy, we agree that our studies suggest a possible role for leptin in obesity hypertension. However, it is unlikely that decreased mineralocorticoid secretion contributes to leptin-induced hypertension; reduced plasma aldosterone and corticosterone would tend to blunt, rather than mediate, the hypertensive effects of leptin.

Our study provides a small step toward elucidating the role of leptin in obesity hypertension. The possibility that leptin is an important regulator of energy balance is widely appreciated, but the role of leptin in mediating the cardiovascular, renal, and endocrine changes associated with increased adiposity is still unclear and deserves further study.

References

1. Shek EW, Brands MW, Hall JE. Chronic leptin infusion increases arterial pressure. Hypertension. 1998;31(pt 2):409–414.

2. Bornstein SR, Uhlmann K, Haidan A, Ehrhart-Bornstein M, Scherbaum WA. Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. Diabetes. 1997;46:1235–1238.

3. Malendowicz LK, Nussdorfer GG, Markowska A. Effects of recombinant murine leptin on steroid secretion of dispersed rat adrenocortical cells. J Steroid Biochem Molec Biol. 1997;63:123–125.[Medline] [Order article via Infotrieve]

4. Young DB, Smith MJ, Jackson TE, Scott RE. Multiplication interaction between angiotensin II and K concentration in stimulation of aldosterone. Am J Physiol. 1984;247:E328–E335.[Abstract/Free Full Text]

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