Department of Nephrology, Endocrinology and Metabolic Diseases, Silesian University School of Medicine, Katowice, Poland
Keywords: adipose tissue; cardiovascular morbidity; obesity
Introduction
Obesity is a challenging health problem in Western societies. It is a risk factor for cardiovascular morbidity and mortality. Recent studies showed that adipose tissue is not only a passive energy store, but also an active endocrine organ, the secretions of which influence the function of many systems. It has been well known for decades that obesity influences the main players of blood pressure regulation, in other words, the heart (increased cardiac output, cardiomyocyte hypertrophy), blood vessels (atherosclerotic changes, increased vascular resistance secondary to hypertrophy of vascular myocytes, increased vascular tone induced by sympathetic activity, abnormal paracrine/autocrine function of the endothelial cells), kidneys (sodium retention, activation of the renal renin-angiotensin system, development of obesity-related glomerulopathy), and the sympathetic nervous system (enhanced activity).
In addition, obesity leads to endocrine, metabolic, haemostatic and haematological abnormalities.
As mentioned above, the adipose tissue is an important endocrine organ producing biologically active substances with local and/or systemic action. An incomplete list comprises PAI-1, transforming growth factor ß (TGF-ß), tissue factor (TF), complement factors (e.g. adipsin), adipocyte complement-related protein (Adipo-a), tumour necrosis factor- (TNF-
), acylation stimulating protein (ASP), angiotensinogen, prostaglandin (PGI 2
), insulin-like growth factor-1 (IGF-1), macrophage inhibitory factor (MIF), sex hormones and glucocorticoids, angiotensin II, leptin, adiponectin and resistin (for review see [1,2]). Adipocytes also have receptors which respond to hormones, cytokines, growth factors and metabolites. The interaction between efferent signals (from adipocytes to other organs) and afferent signals (received by adipocytes) constitutes an elegant feedback system capable of adapting to the numerous challenges of energy metabolism. In this editorial we concentrate on nephrological aspects of some selected secretary products, in other words leptin, adiponectin, TNF-
, resistin and angiotensin II which are all involved in blood pressure regulation and/or target organ damage.
Leptin
Leptin is a protein which is predominantly produced by adipocytes. It is encoded by the ob gene. It is involved in the maintenance of a stable body fat mass. Leptin is important in the regulation of appetite, food intake and energy expenditure, sexual maturation and fertility, haematopoiesis and activity of the hypothalamic-pituitary-gonadal axis. Obese individuals have high plasma leptin concentrations. There is growing evidence that leptin, originally considered exclusively as an anorexigenic hormone, exerts actions in the periphery outside of the central nervous system. Indeed, leptin receptors are found in many tissues including renal tubular cells [3]. These receptors modulate functions such as increasing diuresis and natriuresis, in the absence of changes of blood pressure or potassium excretion. These effects are seen only when high doses of leptin are infused which lead to supraphysiological plasma concentrations [4]. Striking species differences are found with respect to the natriuretic activity of leptin. In the rat, human leptin was natriuretic, but mouse leptin was not [5]. In spontaneously hypertensive rats (SHR) the natriuretic effect of leptin is blunted (tubular leptin resistance) [5]. Leptin also stimulates the activity of the sympathetic nervous system which, in turn, increases tubular sodium reabsorption. High doses of leptin apparently override the antidiuretic and antinatriuretic effects of sympathetic stimulation and thus lead to diuresis and natriuresis.
In the glomerulus, leptin stimulates endocapillary proliferation and mesangial collagen deposition. In cultured rat endothelial cells, mouse recombinant leptin stimulates proliferation and increases TGF-ß mRNA and TGF-ß secretion [6]. Leptin infusion for 3 days increases TGF-ß expression in the rat and causes glomerular endothelial proliferation. Leptin infusion for 3 weeks increases collagen type IV expression [6]. Additionally, leptin stimulates type I collagen production in db/db mesangial cells [7]. It is conceivable that sympathetic activation caused by leptin is involved in the pathogenesis of obesity-related nephropathy [8] because it has recently been shown that sympathetic overactivity contributes to renal damage.
Leptin is mainly eliminated via the kidneys. Consequently, plasma leptin concentrations are markedly higher in patients with chronic renal failure than in healthy subjects [9,10]. Leptin concentrations are normalized by successful kidney transplantation [10]. It was initially thought that hyperleptinaemia was an adequate explanation of anorexia of renal failure. However, subsequent studies addressing the relation between nutritional status and leptin concentration in chronic renal failure yielded conflicting results, showing that the issue is certainly more complex than initially thought.
Leptin stimulates proliferation and differentiation of haemopoietic stem cells [11]. It is likely that the effects of leptin and of erythropoietin (Epo) are synergistic. It deserves consideration whether high leptin concentrations in renal failure counteract the development of anaemia when Epo concentrations decrease.
Leptin influences blood pressure regulation by several mechanisms: activation of the sympathetic nervous system and the pituitary-adrenal axis; influence on the water-electrolyte balance; modulation of endothelial cell function; and influence on vascular remodelling. Leptin contributes to insulin resistance in obese patients [12,13]. Insulin resistance in turn has a hypertensinogenic action. Taking all these actions into consideration it is likely that leptin participates in the pathogenesis of arterial hypertension, as discussed recently in this journal [14]. Further poorly understood actions of leptin concern its role in angiogenesis [15], immune response [16] and bone formation [17], all of which are of potential relevance to the nephrologist.
Adiponectin
Adiponectin is a protein which is specifically expressed in adipocytes. It has high homology to collagens VIII and X, and complement factor C1q. It is a member of the soluble defense collagen family [18] which also includes collectins (mannose-binding lectin (MBL), lung surfactant protein A-SPA, lung surfactant protein D, and conglutin) which are involved in the immune response [19]. The plasma concentrations of adiponectin are relatively high (225 µg/ml) [20]. Adiponectin binds to matrix proteins such as collagen I, III and V, but not collagens II and IV or laminin or fibronectin [21]. This may explain why it accumulates in injured vascular tissue only where it may be involved in the repair process. Adiponectin interferes with TNF--induced endothelial cell NF-
B signalling [22] and inhibits phagocytic activity of macrophages [18]. The plasma concentration of adiponectin is lower in obese than in non-obese subjects [18,23] and it is thought that this negative relation plays a role in atherosclerosis of obese subjects. The initial steps in atherogenesis comprise increased expression of adhesion molecules on endothelial cells, permitting monocyte adhesion and invasion. Adiponectin is thought to inhibit the endothelial expression of adhesion molecules VCAM-1, ICAM-1, and E-selectin, which is triggered by inflammatory cytokines, such as TNF-
. Adiponectin also suppresses production of cytokines, for example TNF-
in macrophages [21,22].
Two atherosclerosis-prone states (i.e. coronary artery disease and diabetes mellitus type 2) are associated with low plasma adiponectin concentrations [25]. The inhibitory effect of adiponectin on the NF-B pathway [22] may contribute to insulin resistance [22,25]. It is unclear, at present, how the expression of adiponectin is regulated. The concentration of adiponectin mRNA increases when pre-adipocytes differentiate to adipocytes. Its concentration is lower in the fat of obese humans and mice than in their non-obese counterparts [24,26]. Plasma adiponectin concentrations are higher in women than in men [20,23] possibly explaining, at least in part, the lower risk of cardiovascular events in women. The role of sex hormones in the regulation of adiponectin expression is unclear.
Preliminary data of Zoccali [27] show that plasma adiponectin levels are increased in uraemic patients. Whether this finding reflects impaired adiponectin clearance by the kidney or is a compensatory mechanism tending to reduce cardiovascular events needs to be elucidated.
Resistin
Resistin is a large polypeptide which is produced exclusively by adipocytes in the mouse [28]. Plasma resistin concentrations are markedly elevated in obese overfed insulin-resistant mice and also in ob/ob and db/db mice with obesity and diabetes mellitus [28]. Neutralization of resistin by anti-resistin antibodies lowers glucose concentrations and improves insulin sensitivity. Conversely, intraperitoneal administration of resistin causes glucose intolerance and insulin resistance in mice. Resistin impairs glucose uptake by adipocytes in vitro. Rosiglitazone, an agonist of peroxisome proliferator-activated receptor- (PPAR-
) reduces gene expression and secretion of resistin [28]. The role of resistin in humans is unknown, but since insulin resistance is a hallmark of diabetes mellitus type 2 and a risk factor for the development of cardiovascular events, this observation may point to new pathophysiological and therapeutic pathways. PPAR-
agonists also protect against non-diabetic glomerulosclerosis in rats by insulin-independent mechanisms [29]. They also improve insulin resistance [30]. These observations may possibly lead to drugs not only for diabetes mellitus type 2, but also for non-diabetic nephropathies.
Tumour necrosis factor
Adipocytes are an important site of TNF- synthesis [31,32]. This cytokine acts on the NF-
B pathway [33] and is involved in the genesis of inflammation or insulin resistance [34]. Excessive TNF-
production in obese patients may contribute to increased cardiovascular morbidity and mortality. Thus, high plasma TNF-
concentrations are associated with insulin resistance, endothelial cell dysfunction, and high C-reactive protein concentrations and IL-6 concentrations in obese subjects [35]. TNF-
also promotes inflammatory and fibrotic processes in the kidneys [33], a finding which is of interest because glomerulopathy is a feature of morbid obesity.
Plasminogen activator inhibitor-1
Adipocytes are a site of abundant PAI-1 synthesis and production [36]. PAI-1 is a pro-coagulative agent and inhibits fibrinolysis. Circulating plasma levels of PAI-1 are an independent predictor of coronary artery disease [37]. These characteristics may explain coronary artery disease in obese patients. Increased PAI concentrations promote release of platelet-derived growth factors which are known to play a role in vascular injury.
The renin-angiotensin system
All components of the renin-angiotensin system are found in adipocytes [38], although it remains possible that some of the components may simply reflect trapping from the circulation. It is unclear to date whether angiotensin II secreted by adipocytes has systemic haemodynamic and/or non-haemodynamic effects [39].
Conclusion
Adipose tissue must, therefore, be considered as a novel endocrine organ with a potential implication in a variety of organ functions. Figure 1 schematically illustrates our present perception of how adipose tissue-derived secretory products (PAI-1, leptin, resistin, adiponectin) may participate in obesity-associated cardiovascular, renal, sympathetic nervous, metabolic, endocrine, haematological and haemostatic complications. We also point to the fact that the different adipocyte secretory products may exert beneficial (adiponectin) or adverse (TNF-
, angiotensin II) effects, by influencing the activity of the NF-
B pathway, a transcription factor of pivotal importance in inflammatory and non-inflammatory processes [32].
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Notes
Correspondence and offprint requests to: Professor Andrzej Wicek, Department of Nephrology, Endocrinology and Metabolic Diseases, Silesian University School of Medicine, Francuska 20/24 Street, PL-40-027 Katowice, Poland. Email: nefro{at}spskm.katowice.pl1
References