sign in sign up
<<
Home , Renin

THE AS A SOURCE OF VASOACTIVE 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 and has been recognised as an active endocrine chronic diseases. organ and a source of many hormones and proinflammatory cytokines in obesity. These Key words: , , , 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, 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, and Leptin glucocorticoids, renin, II, PAI-1, tu- mour necrosis factor-α (TNF-α), interleukin-6, Leptin is a predominantly produced interleukin-8, interleukin-10, interleukin-1ß, acyla- by adipocytes6. It is encoded by the ob gene6. tion stimulating protein (ASP), E2 Initially, leptin was implicated in the regulation of 6 (PGE2), hepatocyte growth factor (HGF), vas- appetite as a satiety . 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 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 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 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 decreases appetite with a subse- +/- +++ 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 . 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 , leptin directly stimulates endoca- patients on haemodialysis33. pillary cell proliferation and mesangial collagen In chronic 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 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 . Plasma leptin concentration may serve in Patients with advanced chronic kidney di- these patients also as a marker of well being36,38. sease (CKD) are characterized by markedly ele- Elucidation of the mechanisms regulating appe- vated plasma leptin concentration compared to tite will be useful in our understanding of cachexia body mass index and sex matched healthy indi- in uremic patients. From the other side it is well viduals26-28. CAPD patient have even higher known that low body mass predominantly mus- plasma leptin concentration than haemodialysis cle mass is combined with the increased mor- patients26,27. However, increased plasma leptin bidity and mortality in these patients. Therefore concentration in CKD is not accounted for by there is no doubt that these new findings on the oversecretion of this hormone. Leptin gene ex- role of leptin in the pathogenesis of cachexia in pression is even lower in adipocytes of CKD uremia may have important clinical and thera- patients than in healthy individuals29. In renal fai- peutic implications35. lure decreased renal of leptin contri- butes to elevated plasma leptin concentrations30. Thus it is not surprising that plasma leptin con- Adiponectin centration is normalized by successful kidney transplantation31. Adiponectin is the cardio protective protein Elimination of leptin is partly independent from hormone secreted almost exclusively by glomerular rate32,33. Kinetic studies sug- adipocytes with antiatherogenic and insulin-sen- gest that the active uptake of the peptide hor- sitizing properties. It shows structural homology mone by the renal tissue contributes to leptin with collagen VIII, X and complement factor catabolism34. Cumin et al.32 studied plasma C1q39. Plasma concentration of adiponectin is leptin in Zucker obese rats subjected to bilateral relatively high (almost 0.01% of total plasma pro- nephrectomy or bilateral ureteral ligation. Follow- tein)40. In contrast to leptin its concentration is ing the bilateral nephrectomy plasma leptin con- lower in obese than in non-obese subjects40. centrations increased by 300%, more than the Lower adiponectinaemia was also found in males 50% increase observed after bilateral ligation of than in females, and in patients with coronary ar- the ureters. Similarly in patients with noninflam- tery disease, diabetes mellitus type II and essen- matory, reversible acute renal failure requiring tial hypertension than in healthy subjects41-43. haemodialysis treatment, plasma leptin concen- Adiponectin receptors are found in skeletal tration although significantly higher than in muscle, and endothelial cells44. It has been

84 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

suggested that adiponectin inhibits formation of main organ participating in the biodegradation initial atherosclerotic lesions by decreasing ex- and elimination of adiponectin from the circula- pression of adhesion molecules (VCAM-1; ICAM- tion. Thus as expected, successful kidney trans- 1, E-selectin) in endothelial cells in response to plantation is accompanied by prompt reduction, inflammatory stimuli such as TNFα45. Adipo- but not normalization, of plasma adiponectin nectin also suppresses production of cytokines, concentration57. In addition an inverse relation- such as TNFα by macrophages46. Moreover, ship between plasma adiponectin concentra- adiponectin suppresses accumulation of lipids tions and GFR was found in patients with es- in human monocyte-derived macrophages and sential hypertension and apparently healthy inhibits transformation of macrophages into foam individuals43,58. Measurements of plasma cells47. It also inhibits cell proliferation stimulated adiponectin concentrations in the renal and by oxydisized LDL and suppresses superoxide of patients with haemodynamically impor- generation48. Finally, adiponectin interferes with tant renal stenosis confirmed the role of atherogenesis in ApoE-deficient mice, a well the kidneys in the elimination of adiponectin59. known model of spontaneous atherosclerosis49. Lower adiponectin gene expression in CKD Adiponectin participates also in the stabili- patients may be partially caused by the micro- sation of atherosclerotic plaques by increasing inflammation. Also in the general population, an expression of tissue inhibitor of metallopro- inverse relationship was found between concen- teinase-1 (TIMP-1) in infiltrating macrophages50. trations of adiponectin and CRP60,61. The same Adiponectin improves insulin sensitivity41 by is true for haemodialysis patients55,62,63. Experi- stimulating glucose utilization and fatty acid oxi- mental studies indicating that TNFα and IL-6 in- dation in skeletal muscles and the liver and by hibit adiponectin gene expression in cultured suppressing enhanced glucose production51. It adipocytes64,65 has already confirmed this clini- has already been shown that low plasma cal observation. adiponectin concentration is an independent pre- Low plasma adiponectin concentration is now dictor of the risk of developing insulin resistance recognised as a new potential risk factor in car- and type 2 diabetes in the general population52. diovascular morbidity and mortality. In a large Adiponectin also modulates inflammatory pro- cohort of hemodialysis patients lower plasma cesses by modifying expression of inflamma- adiponectin concentration was an independent tory cytokines, as shown in the model of anti- predictor of fatal and non-fatal cardiovascular GBM glomerulonephritis53. Adiponectin deficient complications in these patients54,55. mice were more prone to renal injury after ad- ministration of anti-GBM serum53. Plasma adiponectin concentration is almost Resistin 3-times higher in haemodialysis patients with chronic kidney disease then in healthy sub- Resistin is a large polypeptide which is pro- jects54,55. However increased plasma adipo- duced exclusively by adipose tissue matrix66. nectin concentration in these patients could not Plasma resistin concentration is markedly el- be explained by its oversecretion by adipose tis- evated in obese overfed insulin-resistant mice sue, because the expression of the adiponectin and also in ob/ob and db/db mice with obesity gene (ApM1) is decreased in adipocytes of pa- and diabetes mellitus67. In mice, neutralization tients with advanced CKD56. The kidneys are the of resistin by anti-resistin antibodies lowers glu-

Revista Portuguesa de Nefrologia e Hipertensão 85 Jerzy Chudek, Marcin Adamczak, Teresa Nieszporek, Andrzej Więcek

cose concentration and improves insulin sensi- also worth stressing that IL-6 stimulates fibrino- tivity. Conversely, intraperitoneal administration gen production and platelets activity, which in- of resistin causes glucose intolerance and in- creases the risk of clot formation78. sulin resistance in these animals67. Moreover, In CKD patients plasma concentration of resistin impairs glucose uptake by adipocytes IL-6 is higher than in the general population, in vitro. It is important to stress that rosiglitazone, mainly as a consequence of prolonged plasma an agonist of peroxisome proliferator-activated high-life of this cytokine and chronic infections receptor-γ (PPAR-γ), reduces gene expression such as Chlamydia pneumonia and others79. and secretion of resistin67. In spite of this initial Elevated concentration of IL-6 and CRP are both finding in mice, the true role of resistin in hu- strong predictors of mortality in haemodialysis mans is unknown. In humans no association patients80,81. between plasma resistin concentration and adi- posity or insulin resistance has been found68. Similarly to other adipokines, plasma resistin Tumour necrosis factor alpha (TNF-α) concentration is elevated with impairment of the kidney function69. However, no association be- TNF-α is predominantly synthesized by tween plasma resistin concentration and insulin macrophages infiltrating adipose tissue82,83. Sub- sensitivity has been found in these patients69. cutaneous adipose tissue is claimed to produce more TNF-α than visceral one84. This cytokine is involved in the genesis of inflammation and/or Interleukin-6 (IL-6) insulin resistance85. The excess of TNF-α production by adipose IL-6 is one of the main proinflammatory me- tissue is one of many factors influencing insulin diators primarily secreted by the immune sys- resistance, but certainly not a fundamental one. tem cells4. However 20-30% of these cytokines Mice lacking TNF-α or TNF-α receptor function in the circulation is produced by the adipose tis- demonstrate only modest protection against sue70. In obese subjects with high waist-hip ra- hyperglycemia and insulin resistance when tio the participation is even greater70. In was also obese86,87. shown that omental adipose tissue releases 2- There are three mechanisms linking TNF-α 3 times more IL-6 than subcutaneous tissue71. with insulin resistance. The first is related to in- The expression of IL-6 gene is related to the activation of the insulin receptor signaling path- adipose cell size72 and increases postprandi- way (involving NFkB and or INK) by phospho- ally73. Moreover several studies have docu- rylation88,89. The second mechanism engages mented the positive relationship between BMI adiponectin, the secretion of which from and plasma IL-6 concentrations74,75. adipocytes is markedly reduced by TNF-α46. The In the liver, IL-6 stimulates synthesis of acute- third mechanism compromises induction of phase response including C-reactive adipocytes lipolysis and stimulation of hepatic protein (CRP), fibrinogen, serum amyloid-A and lipogenesis90. α-1 antichymotrypsine76. It is already well known The consequence of elevated plasma TNF-α that CRP is both a marker and important risk concentration in CKD patients91 is until now only factor of cardiac events and atherosclerosis in a matter of speculation. the general population and CKD patients77. It is

86 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

Plasminogen activator inhibitor-1 CONCLUSION

Adipose tissue is a site of abundant PAI-1 Visceral adiposity is the key feature of meta- synthesis92. PAI-1 is a pro-coagulative agent and bolic syndrome (Figure 1). Adipokines overse- inhibits fibrinolysis. Circulating plasma level of creted by the excessive amount of visceral adi- PAI-1 is an independent predictor of coronary pose tissue enables us to understand basic artery disease93. These characteristics may ex- metabolic changes related to obesity, such as plain coronary artery disease in obese patients. insulin resistance, dyslipidaemia and chronic Increased PAI concentrations promote release microinflammation. Accelerated atherosclerosis, of platelet-derived growth; factors which are diabetes type 2 and obesity related hypertension known to play a role in vascular injury. are the most frequent causes of morbidity and mortality of the general population. Chronic kid- ney diseases are also common consequence The renin-angiotensin system of diabetic, hypertensive or ischemic nephropa- thies. Only in markedly (morbidly) obese humans All components of the renin-angiotensin sys- obesity per se may directly impair the kidney tem are found in adipose tissue94,95. It is still un- function as an isolated entity – obesity related clear whether angiotensin II secreted by adipose glomerulopathy. tissue has an important systemic haemody- However, even a moderate impairment of kid- namic and/or non-haemodynamic effects96. ney function further increases the risk of cardio- vascular morbidity and mortality97.

Figure 1 – Visceral adiposity and cardiovascular and kidney diseases.

Revista Portuguesa de Nefrologia e Hipertensão 87 Jerzy Chudek, Marcin Adamczak, Teresa Nieszporek, Andrzej Więcek

Therefore it is expected that pharmacologi- 10. Flier JS. : is brain sympathetic to bone? Nature cal intervention in paracrine/endocrine or im- 2002; 420: 619, 621-622. mune activity of the adipose tissue may improve 11. Grinspoon S, Gulick T, Askari H, et al. Serum leptin levels in women with anorexia nervosa. J Clin Endocrinol Metab 1996; the outcome of metabolic syndrome and related, 81: 3861-3863. cardiovascular and renal complications in the 12. Ormseth OA, Nicolson M, Pelleymounter MA, Boyer BB. near future, bringing new hope. Leptin inhibits prehibernation hyperphagia and reduces body weight in arctic ground squirrels. Am J Physiol 1996; 271: Address for correspondence: R1775-R1779. Prof. dr hab. med. Andrzej Wi ę cek , FRCP (Edin) 13. Hwa JJ, Fawzi AB, Graziano MP, et al. Leptin increases Department of Nephrology, Endocrinology and Metabolic energy expenditure and selectively promotes fat metabo- Diseases, lism in ob/ob mice. Am J Physiol 1997; 272: R1204-R1209. Silesian University Medical School, Katowice 14. Gibson WT, Farooqi IS, Moreau M, et al. Congenital leptin ul. Francuska 20/24, deficiency due to homozygosity for the Delta133G muta- 40-027 Katowice, POLAND tion: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab 2004; E-mail: [email protected] 89: 4821-4826. 15. Chehab FF, Mounzih K, Lu R, Lim ME. Early onset of repro- REFERENCES ductive function in normal female mice treated with leptin. Science 1997; 275: 88-90. 1. Havel PJ. Update on adipocyte hormones: regulation of en- 16. Sierra-Honigmann MR, Nath AK, Murakami C, et al. Biologi- ergy balance and carbohydrate/lipid metabolism. Diabetes cal action of leptin as an angiogenic factor. Science 1998; 2004;53:S143. 281: 1683-1686. 2. Wiecekę A, Kokot F, Chudek J, Adamczak M. The adipose 17. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, tissue - a novel endocrine organ of interest to the nephrolo- Lechler RI. Leptin modulates the T-cell immune response gist. Nephrol Dial Transplant 2002;17:191-195. and reverses starvation-induced immunosuppression. Na- 3. Wisse BE. The inflammatory syndrome: the role of adipose ture 1998; 394: 897-901. tissue cytokines in metabolic disorders linked to obesity. J 18. Bornstein SR, Licinio J, Tauchnitz R, et al. Plasma leptin Am Soc Nephrol 2004; 15: 2792-2800. levels are increased in survivors of acute sepsis: associ- 4. Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. Com- ated loss of diurnal rhythm, in and leptin secretion. parison of the release of adipokines by adipose tissue, J Clin Endocrinol Metab 1998; 83: 280-283. adipose tissue matrix, and adipocytes from visceral and 19. Hasty AH, Shimano H, Osuga J, et al. Severe subcutaneous abdominal adipose tissues of obese humans. hypercholesterolemia, hypertriglyceridemia, and atheroscle- Endocrinology 2004; 145: 2273-2282. rosis in mice lacking both leptin and the low density lipopro- 5. Löhn M, Dubrovska G, Lauterbach B, Luft FC, Gollasch M, tein receptor. J Biol Chem 2001; 276: 37402-37408. Sharma AM. Periadventitial fat releases a vascular relaxing 20. Rahmouni K, Haynes WG, Mark AL. Cardiovascular and factor. FASEB J 2002; 16: 1057-1063. sympathetic effects of leptin. Curr Hypertens Rep 2002; 4: 6. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Fried- 119-125. man JM. Positional cloning of the mouse obese gene and its 21. Szanto I, Kahn CR. Selective interaction between leptin and human homologue. Nature 1994; 372: 425-432. insulin signaling pathways in a hepatic cell line. Proc Natl 7. Muzzin P, Eisensmith RC, Copeland KC, Woo SL. Correction Acad Sci USA 2000; 97: 2355–2360. of obesity and diabetes in genetically obese mice by leptin 22. Adamczak M, Kokot F, Wiecekę AW. Relationship between gene therapy. Proc Natl Acad Sci U S A 1996; 93: 14804- plasma renin profile and leptinaemia in patients with essen- 14808. tial hypertension. J Hum Hypertens 2000; 14: 503-950. 8. Horn R, Geldszus R, Potter E, von zur Muhlen A, Brabant G. 23. Kambham N, Markowitz GS, Valeri AM, Lin JK. Obesity- Radioimmunoassay for the detection of leptin in human se- related glomerulopathy: an emerging epidemic. Kidney Int rum. Exp Clin Endocrinol Diabetes 1996; 104: 454-458. 2001; 59: 1498–1509. 9. Caro JF, Kolaczynski JW, Nyce MR, et al. Decreased cer- 24. Wolf G, Hamann A, Han DC, et al. Leptin stimulates prolif- ebrospinal-fluid/serum leptin ratio in obesity: a possible eration and TGF-beta expression in renal glomerular en- mechanism for leptin resistance. Lancet 1996; 348: 159-161. dothelial cells: potential role in glomerulosclerosis. Kidney

88 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

Int 1999; 56: 860–872. and the function of macrophages. Blood 2000; 96: 1723- 25. Han DC, Isono M, Chen S, et al. Leptin stimulates type I 1732. collagen production in db/db mesangial cells. Glucose up- 40. Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an take and TGF-ß type II receptor expression. Kidney Int 2001; adipose-specific protein, adiponectin, in obesity. Biochem 59: 1315–1323. Biophys Res Commun 1999; 257: 79-83. 26. Howard JK, Lord GM, Clutterbucck EJ, et al. Plasma immu- 41. Hotto K, Funahashi T, Arita Y, et al. Plasma concentration of noreactive leptin concentration in endstage renal disease a novel, adipose-specific protein, adiponectin, in type 2 dia- Clin Sci 1997; 93: 119-126. betic patients. Arterioscler Thromb Vasc Biol 2000; 20: 1595– 27. Heimbürger O, Lönnqvist F, Danielsson A, Nordenström J, 1599. Stenvinkel P. Serum immunoreactive leptin concentration and 42. Dzielinskań Z, Januszewicz A, Wiecekę A, et al.: Decreased its relation to the body fat content in chronic renal failure. J plasma concentration of a novel anti-inflammatory protein- Am Soc Nephrol 1997; 8: 1423-1430. adiponectin-in hypertensive men with coronary artery dis- 28. Kokot F, Chudek J, Karkoszka H, Adamczak M, Wiecekę A, ease. Thromb Res 2003; 110: 365-369. Klimek D. Does PTH influence leptin concentration in 43. Adamczak M, Wiecekę A, Funahashi T, Chudek J, Kokot F, haemodialysed uraemic patients? 1999; 82: 372-373. Matsuzawa Y. Decreased plasma adiponectin concentra- 29. Nordfors L, Lönnqvist F, Heimbürger O, Danielsson A, tion in patients with . Am J Hypertens Schalling M, Stenvinkel P. Low leptin gene expression and 2003; 16: 72-75. hyperleptinemia in chronic renal failure. Kidney Int 1998; 54: 44. Yamauchi T, Kamon J, Ito Y, et al. Cloning of adiponectin 1267-1275. receptors that mediate antidiabetic metabolic effects. Na- 30. Cumin F, Baum HP, Levens N. Mechanism of leptin removal ture 2003; 423: 762-769. from the circulation by the kidney. J Endocrinol 1997; 155: 45. Ouchi N, Kihara S, Arita Y, et al. Novel modulator for en- 577-585. dothelial adhesion molecules adipocyte-derived plasma pro- 31. Kokot F, Adamczak M, Wiecekę A. Plasma leptin concentra- tein adiponectin. Circulation 1999; 100: 2473-2476. tion in kidney transplant patients during the early post-trans- 46. Ouchi N, Kihara S, Arita Y et al. Adiponectin and adipocyte- plant period. Nephrol Dial Transplant 1998; 13: 2276-2280. derived plasma protein, inhibits endothelial NF-kappaB 32. Cumin F, Baum HP, de Gasparo M, Levens N. Removal of signaling through a cAMP-dependent pathway. Circulation endogenous leptin from the circulation by the kidney. Int J 2000; 102: 1296–1301. Obes Relat Metab Disord 1997; 21: 495-504. 47. Ouchi N, Kihara S, Arita Y, et al. Adipocyte – derived plasma 33. Ficek R, Kokot F, Chudek J, Adamczak M, Ficek J, Wiecekę A. protein, adiponectin, suppress lipid accumulation and class Plasma leptin concentration in patients with acute renal fail- A receptor expression in human monocyte-derived ure. Clin. Nephrol 2004; 62: 84-91. macrophages. Circulation 2001; 103: 1057-1063. 34. Zeng J, Patterson BW, Klein S, et al. Whole body leptin 48. Motoshima H, Wu X, Mahadev K, Goldstein BJ. Adiponectin kinetics and renal metabolism in vivo. Am J Physiol 1997; suppresses proliferation and superoxide generation and 273: E1102-E1106. enhances eNOS activity in endothelial cells treated with 35. Cheung W, Yu PX, Little BM, Cone RD, Marks DL, Mak RH. oxidized LDL. Biochem Biophys Res Commun 2004; 315: Role of leptin and melanocortin signaling in uremia-associ- 264-271. ated cachexia. J Clin Invest 2005; 115: 1659-1665. 49. Okamoto Y, Kihara S, Ouchi N, et al. Adiponectin reduces 36. Chudek J, Adamczak M, Kania M, et al. Does plasma leptin atherosclerosis in apolipoprotein E-deficient mice. Circula- concentration predict the nutritional status of hemodialyzed tion 2002; 106: 2767-2770. patients with chronic renal failure? Med Sci Monit 2003; 9: 50. Kumada M, Kihara S, Ouchi N, et al. Adiponectin specifically CR377-CR382. increased tissue inhibitor of metalloproteinase-1 through 37. Merabet E, Dagogo-Jack S, Coyne DW, et al. Increased interleukin-10 expression in human macrophages. Circula- plasma leptin concentration in end-stage renal disease. J tion 2004; 109: 2046-2049. Clin Endocrinol Metab 1997; 82: 847-850. 51. Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone 38. Bossola M, Muscaritoli M, Valenza V. et al. Anorexia and adiponectin reverses insulin resistance associated with both serum leptin levels in hemodialysis patients. Nephron Clin lipoatrophy and obesity. Nat Med 2001; 7: 941-946. Pract 2004; 97: c76-c82. 52. Spranger J, Kroke A, Mohlig M. et al. Adiponectin and pro- 39. Yokota T, Oritani K, Ishikawa JTI, et al. Adiponectin, a new tection against type 2 diabetes mellitus. Lancet. 2003; 361: member of the family of soluble defense collagens, nega- 226-228. tively regulates the growth of myelomonocytic progenitors 53. Li P, Wu W, Gersch CM, Feng L. Anti-inflammatory effects

Revista Portuguesa de Nefrologia e Hipertensão 89 Jerzy Chudek, Marcin Adamczak, Teresa Nieszporek, Andrzej Więcek

of adiponectin on anti-GBM glomerulonephritis [abstract]. J 68. Lee JH, Chan JL, Yiannakouris N, et al. Circulating resistin Am Soc Nephrol 2004; 15: 9A. levels are not associated with obesity or insulin resistance 54. Zoccali C, Mallamaci F, Tripepi G, et al. Adiponectin, meta- in humans and are not regulated by fasting or leptin admin- bolic risk factors, and cardiovascular events among pa- istration: cross-sectional and interventional studies in nor- tients with end-stage renal disease. J Am Soc Nephrol mal, insulin-resistant, and diabetic subjects. J Clin Endocrinol 2002;13:134-141. Metab 2003; 88: 4848-4856. 55. Ignacy W, Chudek J, Adamczak M, et al. Reciprocal asso- 69. Kielstein JT, Becker B, Graf S, Brabant G, Haller H, Fliser D. ciation of plasma adiponectin and serum C-reactive protein Increased resistin blood levels are not associated with in- concentration in haemodialysis patients with end-stage kid- sulin resistance in patients with renal disease. Am J Kidney ney disease - a follow-up study. Nephron Clin Pract 2005; Dis 2003; 42: 62-66. 101: c18-c24. 70. Mohamed-Ali V, Goodrick S, Rawesh A, et al. Subcutane- 56. Marchlewska A, Stenvinkel P, Lindholm B, et al. Reduced ous adipose tissue releases interleukin-6, but not tumor gene expression of adiponectin in fat tissue from patients necrosis factor-alpha, in vivo. J Clin Endocrinol Metab 1997; with end-stage renal disease. Kidney Int 2004; 66: 46-50. 82: 4196-4200. 57. Chudek J, Adamczak M, Karkoszka H, et al. Plasma 71. Fried SK, Bunkin DA, Greenberg AS. Omental and subcuta- adiponectin concentration before and after successful kid- neous adipose tissues of obese subjects release interleukin- ney transplantation. Transplant Proc 2003; 35: 2186-2189. 6: depot difference and regulation by glucocorticoid. J Clin 58. Mallamaci F, Zoccali C, Cuzzola F, et al. Adiponectin in es- Endocrinol Metab 1998; 83: 847-850. sential hypertension. J Nephrol 2002; 15: 507-511. 72. Sopasakis VR, Sandqvist M, Gustafson B, et al. High local 59. Adamczak M, Czerwienskań B, Chudek J, Wiecekę A. Role of concentrations and effects on differentiation implicate kidneys in metabolism of adiponectin. studies in patients interleukin-6 as a paracrine regulator. Obes Res 2004; 12: with unilateral stenosis. [Abstract] XLII Con- 454-460. gress ERA-EDTA, Istambul 2005. 73. Orban Z, Remaley AT, Sampson M, Trajanoski Z, Chrousos 60. Ouchi N, Kihara S, Funahashi T, et al. Reciprocal associa- GP. The differential effect of food intake and beta-adrener- tion of C-reactive protein with adiponectin in blood stream gic stimulation on adipose-derived hormones and cytokines and adipose tissue. Circulation 2003; 107: 671-674. in man. J Clin Endocrinol Metab 1999; 84: 2126-2133. 61. Engeli S, Feldpausch M, Gorzelniak K, et al. Association 74. Park HS, Park JY, Yu R. Relationship of obesity and visceral between adiponectin and mediators of inflammation in obese adiposity with serum concentrations of CRP, TNF-alpha and women. Diabetes 2003; 52: 942-947. IL-6. Diabetes Res Clin Pract 2005; 69: 29-35. 62. Huang JW, Yen CJ, Chiang HW, Hung KY, Tsai TJ, Wu KD. 75. Maachi M, Pieroni L, Bruckert E, et al. Systemic low-grade Adiponectin in peritoneal patients: a comparison inflammation is related to both circulating and adipose tis- with hemodialysis patients and subjects with normal renal sue TNFalpha, leptin and IL-6 levels in obese women. Int J function. Am J Kidney Dis 2004; 43: 1047-1055. Obes Relat Metab Disord 2004; 28: 993-997. 63. Lee CT, Lee CH, Su Y, Chuang YC, Tsai TL, Cheni JB. The 76. Zoccali C, Mallamaci F, Tripepi G. Adipose tissue as a source relationship between inflammatory markers, leptin and of inflammatory cytokines in health and disease: focus on adiponectin in chronic hemodialysis patients. Int J Artif Or- end-stage renal disease. Kidney Int 2003; 84 [Suppl]: S65- gans 2004; 27: 835-841. S68. 64. Fasshauer M, Kralisch S, Klier M, et al. Adiponectin gene 77. Burke AP, Tracy RP, Kolodgie F, et al. Elevated C-reactive expression and secretion is inhibited by interleukin-6 in 3T3- protein values and atherosclerosis in sudden coronary death: L1 adipocytes. Biochem Biophys Res Commun 2003; 301: association with different pathologies. Circulation 2002; 105: 1045-1050. 2019-2023. 65. Kappes A, Loffler G.: Influences of ionomycin, dibutyryl- 78. Burstein SA, Peng J, Friese P, et al. Cytokine-induced al- cycloAMP and tumour necrosis factor-alpha on intracellular teration of platelet and hemostatic function. Stem Cells 1996; amount and secretion of apM1 in differentiating primary 14 [Suppl 1]: 154-162. human preadipocytes. Horm Metab Res 2000; 32: 548-554. 79. Jacobs P, Glorieux G, Vanholder R. Interleukin/cytokine pro- 66. Fain JN, Cheema PS, Bahouth SW, Lloyd Hiler M. Resistin files in haemodialysis and in continuous peritoneal dialysis. release by human adipose tissue explants in primary cul- Nephrol Dial Transplant 2004; 19 [Suppl 5]: v41-v45. ture. Biochem Biophys Res Commun 2003; 300: 674-678. 80. Kimmel PL, Phillips TM, Simmens SJ, et al. Immunologic func- 67. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin tion and survival in hemodialysis patients. Kidney Int 1998; links obesity to diabetes. Nature 2001; 18: 307–312. 54: 236-244.

90 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

81. Stenvinkel P, Wanner C, Metzger T, et al. Inflammation and 90. Feingold KR, Grunfeld C. Role of cytokines in inducing outcome in end-stage renal failure: does female gender hyperlipidemia. Diabetes 1992; 41 [Suppl 2]: 97-101. constitute a survival advantage? Kidney Int 2002; 62: 1791- 91. Nishimura M, Hashimoto T, Kobayashi H, et al. Possible in- 1798. volvement of TNF-alpha in left in 82. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, hemodialysis patients. J Nephrol 2003; 16: 641-649. Ferrante AW Jr. Obesity is associated with macrophage 92. Allessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhan- accumulation in adipose tissue. J Clin Invest 2003; 112: 1796- Vague I. Production of plasminogen activator inhibitor-1 by 1808. human adipose tissue: possible link between visceral fat 83. Fain JN, Bahouth SW, Madan AK. TNFalpha release by the accumulation and vascular disease. Diabetes 1997; 46: nonfat cells of human adipose tissue. Int J Obes Relat Metab 860–867. Disord 2004; 28: 616-622. 93. Segarra A, Chacon P, Martinez-Eyarre C, et al. Circulating 84. Winkler G, Kiss S, Keszthelyi L, et al. Expression of tumor levels of plasminogen activator inhibitor type-1, tissue necrosis factor (TNF)-alpha protein in the subcutaneous plasminohen activator, and thrombomodulin in hemodialysis and visceral adipose tissue in correlation with adipocyte patients: biochemical correlations and role as independent cell volume, serum TNF-alpha, soluble serum TNF-receptor- predictors of coronary artery stenosis. J Am Soc Nephrol 2 concentrations and C-peptide level. Eur J Endocrinol 2003; 2001; 12: 1255–1263. 149: 129-135. 94. Gorzelniak K, Engeli S, Janke J, Luft FC, Sharma AM. Hor- 85. Sethi J, Hotamisligil GS. The role of TNF-alfa in adipocyte monal regulation of the human adipose-tissue renin-angi- metabolism. Semin Cell Dev Biol 1999; 10: 19–29. otensin system: relationship to obesity and hypertension. J 86. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Pro- Hypertens 2002; 20: 965-973. tection from obesity-induced insulin resistance in mice lack- 95. Karlsson C, Lindell K, Ottosson M, Sjostrom L, Carlsson B, ing TNF-alpha function. Nature 1997; 389: 610-614. Carlsson LM. Human adipose tissue expresses 87. Ventre J, Doebber T, Wu M, et al. Targeted disruption of the angiotensinogen and required for its conversion tumor necrosis factor-alpha gene: metabolic consequences to angiotensin II. J Clin Endocrinol Metab 1998; 83: 3925- in obese and nonobese mice. Diabetes 1997; 46: 1526- 3929. 1531. 96. Klahr S, Morrissey J. Angiotensin II and gene expression in 88. Hirosumi J, Tuncman G, Chang, et al. A central role for JNK in the kidney. Am J Kidney Dis1998; 31: 171–176. obesity and insulin resistance. Nature 2002; 420: 333-336. 97. Go AS, Chertow GM, Fan D, McCulloh CE, Hsu C. Chronic 89. Hotamisligil GS. Inflammatory pathways and insulin action. kidney disease and the risk of death, cardiovascular events, Int J Obes Relat Metab Disord 2003; 27 [Suppl 3]: S53-S55. and hospitalization. N Engl J Med 2004; 351: 1296-1305.

Revista Portuguesa de Nefrologia e Hipertensão 91