THE ADIPOSE TISSUE AS A SOURCE OF VASOACTIVE HORMONES AND CYTOKINES WITH A POTENTIAL ReviewROLE IN THE Article PATHOGENESIS OF CARDIOVASCULAR AND RENAL DISEASES Rev Port Nefrol Hipert 2006; 20 (2): 81-91 The adipose tissue as a source of vasoactive hormones and cytokines with a potential role in the pathogenesis of cardiovascular and renal diseases Jerzy Chudek, Marcin Adamczak, Teresa Nieszporek, Andrzej Więcek Department of Nephrology, Endocrinology and Metabolic Diseases. Medical University of Silesia, Katowice, Poland SUMMARY In this review we have summarized the present knowledge of some adipokines in pa- During the last decade white adipose tissue tients with obesity, arterial hypertension and has been recognised as an active endocrine chronic kidney diseases. organ and a source of many hormones and proinflammatory cytokines in obesity. These Key words: leptin, adiponectin, resistin, adipokines may play an important role in the interleukin-6, TNF-alpha, cardio-vascular. pathogenesis of cardio-vascular and kidney di- seases. The contribution to the vascular pathology of INTRODUCTION obesity of different cell types which compose the adipose tissue; adipocytes, preadipocytes, stro- The epidemic of visceral obesity, insulin re- mal/vascular cells and macrophages, is, how- sistance, noninsulin-dependent diabetes mellitus ever, different. and obesity related arterial hypertension is a challenging health problem for modern socie- ties. No solution to the increasing danger posed Received for publication: 24/08/2005 by these well known risk factors of cardiovas- Accepted: 14/09/2005 cular morbidity and mortality has been yet pro- Revista Portuguesa de Nefrologia e Hipertensão 81 Jerzy Chudek, Marcin Adamczak, Teresa Nieszporek, Andrzej Więcek posed. Propagation of an active life style and low influence the vascular tonus and arterial blood caloric diet as well as anorexigenic medications pressure5. are still insufficient to counterbalance an easy The knowledge of adiposity related mecha- approach to high caloric products. nisms devastating the cardio-vascular system The last decade has seen adipose tissue re- and the kidneys may help in the design of new discovered as an active endocrine organ and an drugs for the prevention and treatment of the important source of several proinflammatory metabolic syndrome. The role of some adipo- cytokines1,2. Several of these may directly influ- kines in the pathogenesis of cardio-vascular and ence the function of the cardio-vascular system renal diseases is discussed in this review. and the atherosclerosis process. An incomplete list of adipokines would run as follows: leptin, adiponectin and resistin, estrogens and Leptin glucocorticoids, renin, angiotensin II, PAI-1, tu- mour necrosis factor-α (TNF-α), interleukin-6, Leptin is a protein predominantly produced interleukin-8, interleukin-10, interleukin-1ß, acyla- by adipocytes6. It is encoded by the ob gene6. tion stimulating protein (ASP), prostaglandin E2 Initially, leptin was implicated in the regulation of 6 (PGE2), hepatocyte growth factor (HGF), vas- appetite as a satiety hormone . It was found that cular endothelial growth factor (VEGF), insulin rats with homozygous nonsense mutation of the growth factor-1 (IGF-1), tissue factor (TF), com- ob gene were suffering from marked obesity, plement factor D (adipsin), Agouti signaling pro- while parenteral leptin substitution was decreas- tein (ASP), nitric oxide (NO)3. ing their appetite and body mass7. A few years Adipose tissue is not a homogenous organ. later leptin appeared mostly as a marker of nu- It consists of a variety of different cell types such trition unable to decrease food intake in obese as adipocytes, preadipocytes, stromal/vascular humans, as opposed to what was initially ex- cells and macrophages3 (Table I). Each of these pected. Obese individuals, especially females, cells present their own secretion profile and spe- are characterised by high plasma leptin concen- cific regulation. It is already well known that ma- trations8. Thus even highly elevated plasma leptin ture adipocytes are the main source of leptin and concentration does not suppress the appetite in adiponectin, that macrophages produce almost these individuals9. 10 all TNF-α, while PGE2, interleukins, VEGF, HGF According to Flier , leptin should not be re- are synthesized by stromal and vascular cells3,4. garded as an antiobesity hormone but as a sign There are also some differences in the of energy deficiency and integrator of neuroen- adipokines production between visceral and pe- docrine function. Low plasma leptin concentra- ripheral fat tissue (Table II). Adipokines released tion – a ‘starvation signal’ – modulates the from the fat tissue may exert their action on the hypothalamic-pituitary-adrenal axis, suppresses endocrine, paracrine or autocrine pattern. While thyroid and gonadal axes10. These endocrine this review mainly focuses on a discussion of changes resemble the clinical status of patients the endocrine action of adipokines, the paracrine with anorexia nervosa11. action can not be neglected in cardio-vascular Low plasma leptin concentration decreases diseases. An example of this is secretion of NO energy expenditure and stimulates the search by the periadventitial fat tissue5. Its action on the for food in deprived of food rodents12,13. Only in neighbouring smooth muscle cells may actively animals with low body fat stores it was demons- 82 Revista Portuguesa de Nefrologia e Hipertensão THE ADIPOSE TISSUE AS A SOURCE OF VASOACTIVE HORMONES AND CYTOKINES WITH A POTENTIAL ROLE IN THE PATHOGENESIS OF CARDIOVASCULAR AND RENAL DISEASES TABLE I trated that leptin is involved in the regulation of The most important adipokines released by adipocytes and food intake and energy expenditure. Similarly, the matrix of adipose tissue only in obese children with inactivating mutations Adipocytes Tissue matrix of both leptin alleles, parenteral substitution of this peptide decreases appetite with a subse- Prostaglandin E2 +/- +++ quent reduction of body mass14. Prostacycline +/- +++ It is well known that sexual maturation and Adiponectin +++ + fertility are linked to nutritional status and adi- Leptin +++ - posity. Injection of leptin in the prepubertal fe- Resistin + +++ male mouse causes earlier maturation of the 15 Interleukin 8 + +++ reproductive tract , suggesting that leptin acts as a signal for puberty. Moreover leptin may pro- Interleukin 6 +/- +++ mote angiogenesis and stimulate proliferation Interleukin 10 +/- +++ and differentiation of haemopoietic cells, inclu- Interleukin 1ß +/- +++ ding T cells16,17. In acute infections the shift of Tumor necrosis factor α (TNF-α)+/-+++the immune system, stimulated by leptin, toward Platelet activator inhibitor 1 (PAI-1) ++ +++ the predominance of the proinflammatory Th1 T cells population seems to be beneficial18. Hepatocyte growth factor (HGF) +/- +++ Chronic stimulation of the immune system by Vascular epithelial growth factor (VEFG) +/- +++ leptin may lead to acceleration of atherosclero- Angiotensin II + +++ sis, as leptin-deficient mice are protected from atherosclerosis despite all the other metabolic factors that contribute to this vascular disease19. In obese humans leptin exerts a deteriorative impact on the cardiovascular system and kid- TABLE II neys by significant contribution to the Comparison of gene expression of adipokines by adipocytes pathogenesis of obesity related arterial hyper- in human visceral or subcutaneous adipose tissue tension. It was shown that high plasma leptin concentration stimulates the activity of the sym- Visceral Subcutaneous pathetic nervous system via the receptors lo- Leptin + ++ cated in the brain trunk20. Moreover, leptin exa- ggerates insulin resistance in obese patients21, Adiponectin +++ + stimulates activity of the renin-angiotensin sys- IL-6 +++ + tem22 and modulates the function of endothelial cell (vascular remodelling)16. Many of these TNF-α ++ above mentioned mechanisms interfere with the PAI-1 ++ + tubular sodium reabsorption. The contra-regu- latory mechanisms responsible for the lack of Angiotensinogen ++ + arterial hypertension in 10-20 % of obese hu- Estrogens + + mans were not identified. Leptin is also involved in the pathogenesis of IGF-1 + + obesity-related nephropathy and the progression Revista Portuguesa de Nefrologia e Hipertensão 83 Jerzy Chudek, Marcin Adamczak, Teresa Nieszporek, Andrzej Więcek of chronic glomerulopaties23. Within the healthy subjects was much lower than in CKD glomerulus, leptin directly stimulates endoca- patients on haemodialysis33. pillary cell proliferation and mesangial collagen In chronic uremia elevated plasma leptin con- typ I and IV deposition24,25. In cultured rat endothe- centration seems to participate in the lial cells, mouse recombinant leptin stimulates pathogenesis of uremia-associated cachexia via proliferation and increases TGF-ß mRNA and signaling through the central melanocortin sys- TGF-ß secretion24. It also stimulates the expres- tem35. On the other hand, it should be stressed sion of TGF receptors24. Leptin infusion in rats that studies addressing the influence of plasma enhances urinary protein excretion24. In addition, leptin concentration on future changes of the leptin induces overactivity of the sympathetic body mass in hemodialysis patients failed to find nervous, that may contribute to renal damage such a relationship36,37. directly or indirectly via elevated blood pressure. Plasma leptin concentration may serve in Patients with advanced chronic