CCA-13531; No of Pages 2 Clinica Chimica Acta xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Letter to the Editor
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Annexin A1 concentrations is decreased in patients with diabetes type 2 and nephropathy
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Acknowledgments
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The diabetic nephropathy is considered an inflammatory process characterized by macrophage infiltration observed in every stage of renal involvement. In addition, pro-inflammatory cytokines and adhesion molecules are important in the development of the disease [1]. Annexin A1 (AnxA1) is a 37-kDa protein that regulates various cellular functions and binds to phospholipids in a calcium-dependent manner. Glucocorticoids (GC) regulate expression of ANXA1, which in turn mediates GC's anti-inflammatory actions; however, its expression is also contra-regulated by proinflammatory cytokines, as IL-6. AnxA1 presents anti-inflammatory properties, inhibiting distinct stages of the leukocyte transmigration cascade and interacting directly with NF-κB in an intracellular manner to reduce proinflammatory pathways [2]. AnxA1 has also proresolving properties including promotion of efferocytosis of apoptotic polymorphonuclear leucocytes and is widely present in soluble form in plasma. Some studies have suggested that AnxA1 deficiency may contribute to the etiology of inflammatory diseases [3,4]. We evaluated the AnxA1 concentrations in T2D patients with and without nephropathy and the correlation with IL-6 concentrations. We studied 4 T2D patients without nephropathy (mean age = 46 ± 12 years, 3 women) and 35 T2D patients with nephropathy (mean age = 56 ± 8 years, 31 women), recruited from Santa Casa Hospital (Belo Horizonte, Minas Gerais, Brazil) in the period of June 2012 to
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Dear Editor,
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September 2013. Diabetic nephropathy was defined as albumin excretion rate (AER) N 30 mg/24 h and without coexisting renal diseases from causes other than diabetes. No nephropathy, a less frequent condition among T2D patients, was defined as an AER b 30 mg/24 h, at least 2 out of 3 urine collections over a 3-month period. Subjects older than 70 years, with cancer or autoimmune disease, with current or recent infectious process, with history of cardiovascular disease, and with treatment of anti-inflammatory drugs were excluded. The concentrations of AnxA1 (USCN Life Sciences Inc) and IL-6 (Quantikine HS High sensitivity human IL-6 kit; R&D Systems) were measured in serum, by ELISA, according to the manufacturer's instructions. The study was approved by the Ethics Committee of the Federal University of Minas Gerais. Informed consent was obtained from all patients. AnxA1 concentrations in T2D patients without nephropathy (265.6 ± 41.5 ng/ml) were higher than those in T2D patients with this complication (151.0 ± 84.6 ng/ml; p = 0.026 — Student's t test) (Fig. 1). Regarding the proinflammatory cytokine IL-6, no difference was observed when compared the 2 groups (nephropathy: 5.3 + 3.9; no nephropathy: 7.3 + 5.2; p = NS). However, a positive and strong correlation was observed between AnxA1 and IL-6 concentrations (r2 = 0.200; p = 0.004 — Pearson Correlation Coefficient). These results indicate that the anti-inflammatory and proresolving properties of AnxA1 may be compromised or attenuated with the nephropathy occurrence, a phenomenon also observed in other chronic inflammatory disease [3,4]. Moreover, the significant correlation between the circulating concentrations of AnxA1 and IL-6 suggests higher AnxA1 production in presence of the pro-inflammatory markers, acting as a counter-regulatory tool for dealing with the inflammatory stimulus, characterized by the IL-6 release. As inflammation is a hallmark of diabetic nephropathy, proresolving therapeutics may have potential benefit for the treatment of this complication by attenuating renal fibrosis [5], which suggests that the administration of pro-resolving agents such as AnxA1 or its agonists could be an effective therapy for delay the nephropathy development in T2D patients.
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1
Fig. 1. Annexin A1 (AnxA1) concentrations for Type 2 diabetic patients with and without nephropathy. (Data are presented in ng/ml. *p b 0.05).
32 33 34 35 36 37 38 Q1 39 40 41 42 43 44 45 46 Q2 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
CNPQ and FAPEMIG/Brazil. ALT, LPS and KBG are grateful to CNPq 67 Research Fellowship (PQ). 68 References
69
[1] Gomes KB, Rodrigues KF, Fernandes AP. The role of transforming growth factor-beta (TGF-Beta) in diabetic nephropathy. Int J Med Genet 2014;1:1–6. [2] de Coupade C, Ajuebor MN, Russo-Marie F, Perretti M, Solito E. Cytokine modulation of liver annexin 1 expression during experimental endotoxemia. Am J Pathol 2001;159:1435–43. [3] Kosicka A, Cunliffe AD, Mackenzie R, et al. Attenuation of plasma annexin A1 in human obesity. FASEB J 2013;27:368–78. [4] Vong L, Ferraz JG, Dufton N, et al. Up-regulation of Annexin-A1 and lipoxin A(4) in individuals with ulcerative colitis may promote mucosal homeostasis. PLoS One 2012;7:e39244. [5] Börgeson E, Docherty NG, Murphy M, et al. Lipoxin A4 and benzo-lipoxin A4 attenuate experimental renal fibrosis. FASEB J 2011;25:2967–79.
70 71 72 73 74 75 76 77 78 79 80 81
http://dx.doi.org/10.1016/j.cca.2014.05.027 0009-8981/© 2014 Published by Elsevier B.V.
Please cite this article as: Pietrani NT, et al, Annexin A1 concentrations is decreased in patients with diabetes type 2 and nephropathy, Clin Chim Acta (2014), http://dx.doi.org/10.1016/j.cca.2014.05.027
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Antônio L. Teixeira Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Marina C. Oliveira Faculdade de Enfermagem, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Adriana A. Bosco Santa Casa de Belo Horizonte, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Karina B. Gomes Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil Corresponding author at: Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais. Av. Antônio Carlos, 6627, Pampulha Belo Horizonte, MG 31270-901, Brazil. Tel.: +55 31 3409 6895; fax: +55 31 3409 6985. E-mail address: [email protected].
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Kathryna F. Rodrigues Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Lirlândia P. Sousa Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Cláudia N. Ferreira Colégio Técnico — COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Adaliene V. Ferreira 106 Faculdade de Enfermagem, Universidade Federal de Minas Gerais, 107 Belo Horizonte, Minas Gerais, Brazil 108
Nathalia T. Pietrani Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Letter to the Editor
Please cite this article as: Pietrani NT, et al, Annexin A1 concentrations is decreased in patients with diabetes type 2 and nephropathy, Clin Chim Acta (2014), http://dx.doi.org/10.1016/j.cca.2014.05.027
128
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Letter to the Editor
2 3 4
Annexin A1 concentrations is decreased in patients with diabetes type 2 and nephropathy
24 25 26 27 28 29 30
C
22 23
E
20 21
R
18 19
R
16 17
N C O
14 15
U
Acknowledgments
66
R O
12 13
P
The diabetic nephropathy is considered an inflammatory process characterized by macrophage infiltration observed in every stage of renal involvement. In addition, pro-inflammatory cytokines and adhesion molecules are important in the development of the disease [1]. Annexin A1 (AnxA1) is a 37-kDa protein that regulates various cellular functions and binds to phospholipids in a calcium-dependent manner. Glucocorticoids (GC) regulate expression of ANXA1, which in turn mediates GC's anti-inflammatory actions; however, its expression is also contra-regulated by proinflammatory cytokines, as IL-6. AnxA1 presents anti-inflammatory properties, inhibiting distinct stages of the leukocyte transmigration cascade and interacting directly with NF-κB in an intracellular manner to reduce proinflammatory pathways [2]. AnxA1 has also proresolving properties including promotion of efferocytosis of apoptotic polymorphonuclear leucocytes and is widely present in soluble form in plasma. Some studies have suggested that AnxA1 deficiency may contribute to the etiology of inflammatory diseases [3,4]. We evaluated the AnxA1 concentrations in T2D patients with and without nephropathy and the correlation with IL-6 concentrations. We studied 4 T2D patients without nephropathy (mean age = 46 ± 12 years, 3 women) and 35 T2D patients with nephropathy (mean age = 56 ± 8 years, 31 women), recruited from Santa Casa Hospital (Belo Horizonte, Minas Gerais, Brazil) in the period of June 2012 to
D
7
E
Dear Editor,
T
6
10 11
31
O
5
8 9
September 2013. Diabetic nephropathy was defined as albumin excretion rate (AER) N 30 mg/24 h and without coexisting renal diseases from causes other than diabetes. No nephropathy, a less frequent condition among T2D patients, was defined as an AER b 30 mg/24 h, at least 2 out of 3 urine collections over a 3-month period. Subjects older than 70 years, with cancer or autoimmune disease, with current or recent infectious process, with history of cardiovascular disease, and with treatment of anti-inflammatory drugs were excluded. The concentrations of AnxA1 (USCN Life Sciences Inc) and IL-6 (Quantikine HS High sensitivity human IL-6 kit; R&D Systems) were measured in serum, by ELISA, according to the manufacturer's instructions. The study was approved by the Ethics Committee of the Federal University of Minas Gerais. Informed consent was obtained from all patients. AnxA1 concentrations in T2D patients without nephropathy (265.6 ± 41.5 ng/ml) were higher than those in T2D patients with this complication (151.0 ± 84.6 ng/ml; p = 0.026 — Student's t test) (Fig. 1). Regarding the proinflammatory cytokine IL-6, no difference was observed when compared the 2 groups (nephropathy: 5.3 + 3.9; no nephropathy: 7.3 + 5.2; p = NS). However, a positive and strong correlation was observed between AnxA1 and IL-6 concentrations (r2 = 0.200; p = 0.004 — Pearson Correlation Coefficient). These results indicate that the anti-inflammatory and proresolving properties of AnxA1 may be compromised or attenuated with the nephropathy occurrence, a phenomenon also observed in other chronic inflammatory disease [3,4]. Moreover, the significant correlation between the circulating concentrations of AnxA1 and IL-6 suggests higher AnxA1 production in presence of the pro-inflammatory markers, acting as a counter-regulatory tool for dealing with the inflammatory stimulus, characterized by the IL-6 release. As inflammation is a hallmark of diabetic nephropathy, proresolving therapeutics may have potential benefit for the treatment of this complication by attenuating renal fibrosis [5], which suggests that the administration of pro-resolving agents such as AnxA1 or its agonists could be an effective therapy for delay the nephropathy development in T2D patients.
F
1
Fig. 1. Annexin A1 (AnxA1) concentrations for Type 2 diabetic patients with and without nephropathy. (Data are presented in ng/ml. *p b 0.05).
32 33 34 35 36 37 38 Q1 39 40 41 42 43 44 45 46 Q2 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
CNPQ and FAPEMIG/Brazil. ALT, LPS and KBG are grateful to CNPq 67 Research Fellowship (PQ). 68 References
69
[1] Gomes KB, Rodrigues KF, Fernandes AP. The role of transforming growth factor-beta (TGF-Beta) in diabetic nephropathy. Int J Med Genet 2014;1:1–6. [2] de Coupade C, Ajuebor MN, Russo-Marie F, Perretti M, Solito E. Cytokine modulation of liver annexin 1 expression during experimental endotoxemia. Am J Pathol 2001;159:1435–43. [3] Kosicka A, Cunliffe AD, Mackenzie R, et al. Attenuation of plasma annexin A1 in human obesity. FASEB J 2013;27:368–78. [4] Vong L, Ferraz JG, Dufton N, et al. Up-regulation of Annexin-A1 and lipoxin A(4) in individuals with ulcerative colitis may promote mucosal homeostasis. PLoS One 2012;7:e39244. [5] Börgeson E, Docherty NG, Murphy M, et al. Lipoxin A4 and benzo-lipoxin A4 attenuate experimental renal fibrosis. FASEB J 2011;25:2967–79.
70 71 72 73 74 75 76 77 78 79 80 81
http://dx.doi.org/10.1016/j.cca.2014.05.027 0009-8981/© 2014 Published by Elsevier B.V.
Please cite this article as: Pietrani NT, et al, Annexin A1 concentrations is decreased in patients with diabetes type 2 and nephropathy, Clin Chim Acta (2014), http://dx.doi.org/10.1016/j.cca.2014.05.027
2
F
O
R O
112 113 114 115
118 119 120 121 122 123 124 125
14 April 2014 126 Available online xxxx 127
P
104
Antônio L. Teixeira Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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102 103
E
100 101
Marina C. Oliveira Faculdade de Enfermagem, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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98 99
C
96 97
Adriana A. Bosco Santa Casa de Belo Horizonte, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
116 117
E
94 95
Karina B. Gomes Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil Corresponding author at: Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais. Av. Antônio Carlos, 6627, Pampulha Belo Horizonte, MG 31270-901, Brazil. Tel.: +55 31 3409 6895; fax: +55 31 3409 6985. E-mail address: [email protected].
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Kathryna F. Rodrigues Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
110 111
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90 91
Lirlândia P. Sousa Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Cláudia N. Ferreira Colégio Técnico — COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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86 87
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Adaliene V. Ferreira 106 Faculdade de Enfermagem, Universidade Federal de Minas Gerais, 107 Belo Horizonte, Minas Gerais, Brazil 108
Nathalia T. Pietrani Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
U
82 83
Letter to the Editor
Please cite this article as: Pietrani NT, et al, Annexin A1 concentrations is decreased in patients with diabetes type 2 and nephropathy, Clin Chim Acta (2014), http://dx.doi.org/10.1016/j.cca.2014.05.027
128
