Previous studies have indicated that the LRb leptin receptor is localized in the renal medulla [20
] which suggests a functional role of this hormone in renal biology. In the last 5–10 years, numerous studies have demonstrated that acute administration of synthetic leptin in the rat produces a significant elevation in urinary sodium and water excretion [14
Villarreal et al. [14
] demonstrated that in normotensive rats, an intravenous bolus of leptin produced a robust six to sevenfold elevation in urinary sodium excretion and fractional excretion of sodium; in contrast, hypertensive rats were refractory to the renal effects of leptin. Interestingly, the natriuretic effect was attenuated in obese Zucker rats [14
]. MAP and creatinine clearance remained unchanged in all of the rat strains with the acute infusion of the hormone. Collectively, these findings were interpreted to suggest that leptin might be a natriuretic hormone primarily acting at the tubular level for promotion of sodium and water excretion in normal rats, and that leptin may function pathophysiologically in obesity and hypertension, where chronic hyperleptinemia may contribute to a preferential stimulation of the sympathetic nervous system with further elevation in blood pressure and reduced sodium and water excretion [2
]. Moreover, in a rat model of diet-induced obesity, initial studies by Patel et al. have shown markedly attenuated natriuretic and diuretic effects of synthetic leptin as well as reduced urinary excretion of NO [51
]. These findings suggest that in obesity, alterations in leptin-induced renal NO production and/or metabolism may account, at least in part, for the blunted natriuretic effects. However, additional observations in diet-induced obese rats indicate that caloric restriction was associated with the restoration of the natriuretic actions of leptin as well as with the renal generation of NO [51
]. In the aggregate, these studies are consistent with the concept that obesity is associated with renal leptin resistance [14
], and this resistance, at least in part, is reversible with caloric restriction and weight loss.
The significance of NO in the direct modulation of leptin-induced sodium excretion has been investigated in rats chronically treated with L-NAME to inhibit NO production [53
]. L-NAME-treated rats failed to produce significant natriuresis. However, there was a two to threefold elevation in sodium excretion induced by leptin with the restoration of NO by sodium nitroprusside [53
], indicating that NO may play an important role in mediating or modulating the tubular natriuretic effects of leptin. These observations are supported by the studies of Beltowski et al., [52
] which demonstrated that leptin produces a time- and dose-dependent reduction of renal medullary Na-K-ATPase, which may in part be regulated by NO [53
]. Beltowski et al., [52
] also reported that in diet-induced obese rats, leptin-induced stimulation of plasma NO, reduction of renal Na-K-ATPase, and natriuresis are all significantly impaired.
The mechanisms for renal resistance to leptin in obesity and hypertension are not completely defined but may include receptor down regulation [12
], postreceptor signaling alterations [12
], excessive degradation of NO produced by oxidative stress [55
], or increased activation of the efferent renal sympathetic nervous system leading to antinatriuresis [49
]. Indeed, studies which [49
] have examined this latter hypothesis using an animal model of renal denervation indicate that the renal efferent sympathetic nervous system is an important counter-regulatory mechanism impeding leptin-induced sodium excretion in hypertension, and perhaps also during obesity, which is similarly characterized by a heightened sympathetic nervous tone [2
The relevance of endogenous leptin as a distinct sodium-volume regulatory hormone has been examined in normal Sprague Dawley rats that were in a state of mild sodium/volume expansion [56
]. Urinary sodium and volume excretion were significantly reduced by approximately 20–25% after blockade of leptin with a polyclonal antibody, indicating an important physiologic role for this hormone in the daily renal control of salt and water balance. The importance of leptin as a regulator of sodium and volume is further supported by recent investigations [56
] which have demonstrated that leptin expression in adipose tissue is directly proportional to dietary sodium, a response that would be expected for mechanisms regulating sodium balance.
Thus, the available information to date suggests that leptin's net effect on renal sodium metabolism and ultimately systemic hemodynamics may reflect both direct natriuretic and indirect antinatriuretic actions. The responsiveness to leptin at neural, renal, and other sites which regulate natriuresis and vascular resistance may differ under diverse physiological and pathophysiological conditions, and this in turn, will be a determinant for the overall magnitude of leptin-induced sodium, water, and hemodynamic balance.