Background. We recently demonstrated high urine levels of annexin A1 (ANXA1) protein in a mouse Adriamycin-induced glomerulopathy (ADG) model. Objective. To establish ANXA1 as a potential biomarker for glomerular injury in patients. Methods. A time-course study in the mouse ADG model, followed by renal tissues and urine samples from patients with various types of glomerular disorders for ANXA1. Results. Urinary ANXA1 protein was (1) detectable in both the ADG model and in patients except those with minimal change disease (MCD); (2) positively correlated with renal lesions in patients; and (3) early detectable in diabetes patients with normoalbuminuria. Conclusions. ANXA1 is a universal biomarker that is helpful in the early diagnosis, prognostic prediction, and outcome monitoring of glomerular injury. Measurement of urinary ANXA1 protein levels can help in differentiating MCD from other types of glomerular disorders. 1. Introduction Despite their well-known limitations, currently, the most widely used biomarkers for the early detection of chronic kidney disease or acute kidney injury are proteinuria, serum creatinine (Cr), and blood urea nitrogen (BUN). However, all of these indexes are less than optimal and are probably more relevant to later stages of injury, when therapeutic responses might be poor. The value of using serum Cr or albuminuria as a reliable urinary marker is being increasingly challenged in terms of its prediction value in certain renal conditions [1, 2]. In addition, regardless of the type of glomerular disorder, neither albumin nor Cr is produced in the kidney. Recently, there has been great interest in strategies aimed at identifying novel biomarkers that can be easily detected in a noninvasive way (such as the use of urine samples) and can predict renal damage during the earlier stages [3]. Glomerular disorders represent a major health care problem because of their high mortality and morbidity rates [4]. Several studies have demonstrated that glomerular disorders are a multifactorial process caused by immune and nonimmune mechanisms that lead to glomerulosclerosis, tubulointerstitial fibrosis, inflammatory infiltration, loss of renal parenchyma, and renal vascular changes [5, 6]. Although glomerular disorders can cause significant morbidity and mortality, they are treatable and constitute a preventable cause of renal failure and cardiovascular risk [7]. Importantly, the early recognition of the disease and the timely institution of appropriate treatment for patients with glomerular disorders should be beneficial. We recently
References
[1]
A. Ishani, G. A. Grandits, R. H. Grimm et al., “Association of single measurements of dipstick proteinuria, estimated glomerular filtration rate, and hematocrit with 25-year incidence of end-stage renal disease in the multiple risk factor intervention trial,” Journal of the American Society of Nephrology, vol. 17, no. 5, pp. 1444–1452, 2006.
[2]
W. F. Keane, Z. Zhang, P. A. Lyle et al., “Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy: the RENAAL study,” Clinical journal of the American Society of Nephrology, vol. 1, no. 4, pp. 761–767, 2006.
[3]
M. H. Rosner, “Urinary biomarkers for the detection of renal injury,” Advances in clinical chemistry, vol. 49, pp. 73–97, 2009.
[4]
J. R. Timoshanko and P. G. Tipping, “Resident kidney cells and their involvement in glomerulonephritis,” Current Drug Targets: Inflammation and Allergy, vol. 4, no. 3, pp. 353–362, 2005.
[5]
A. B. Fogo, “Mechanisms of progression of chronic kidney disease,” Pediatric Nephrology, vol. 22, no. 12, pp. 2011–2022, 2007.
[6]
J. L. Olson and R. H. Heptinstall, “Biology of disease. Nonimmunologic mechanisms of glomerular injury,” Laboratory Investigation, vol. 59, no. 5, pp. 564–578, 1988.
[7]
P. W. Mathieson, “Glomerulonephritis: is it worth worrying about?” Clinical Medicine, vol. 5, no. 3, pp. 264–266, 2005.
[8]
H.-A. Shui, T.-H. Huang, S.-M. Ka, P.-H. Chen, Y.-F. Lin, and A. Chen, “Urinary proteome and potential biomarkers associated with serial pathogenesis steps of focal segmental glomerulosclerosis,” Nephrology Dialysis Transplantation, vol. 23, no. 1, pp. 176–185, 2008.
[9]
C.-W. Cheng, A. Rifai, K. A. Shuk-Man et al., “Calcium-binding proteins annexin A2 and S100A6 are sensors of tubular injury and recovery in acute renal failure,” Kidney International, vol. 68, no. 6, pp. 2694–2703, 2005.
[10]
S.-M. Ka, A. Rifai, J.-H. Chen et al., “Glomerular crescent-related biomarkers in a murine model of chronic graft versus host disease,” Nephrology Dialysis Transplantation, vol. 21, no. 2, pp. 288–298, 2006.
[11]
V. Gerke and S. E. Moss, “Annexins: from structure to function,” Physiological Reviews, vol. 82, no. 2, pp. 331–371, 2002.
[12]
A. C. Rintala-Dempsey, A. Rezvanpour, and G. S. Shaw, “S100-annexin complexes—structural insights,” The FEBS Journal, vol. 275, no. 20, pp. 4956–4966, 2008.
[13]
L. H. K. Lim and S. Pervaiz, “Annexin 1: the new face of an old molecule,” The FASEB Journal, vol. 21, no. 4, pp. 968–975, 2007.
[14]
M. Perretti and R. J. Flower, “Annexin 1 and the biology of the neutrophil,” Journal of Leukocyte Biology, vol. 76, no. 1, pp. 25–29, 2004.
[15]
M. Perretti and F. N. E. Gavins, “Annexin 1: an endogenous anti-inflammatory protein,” News in Physiological Sciences, vol. 18, no. 2, pp. 60–64, 2003.
[16]
L. Tatenhorst, U. Rescher, V. Gerke, and W. Paulus, “Knockdown of annexin 2 decreases migration of human glioma cells in vitro,” Neuropathology and Applied Neurobiology, vol. 32, no. 3, pp. 271–277, 2006.
[17]
Q. Ling, A. T. Jacovina, A. Deora et al., “Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo,” Journal of Clinical Investigation, vol. 113, no. 1, pp. 38–48, 2004.
[18]
Y. Biener, R. Feinstein, M. Mayak, Y. Kaburagi, T. Kadowaki, and Y. Zick, “Annexin II is a novel player in insulin signal transduction: possible association between annexin II phosphorylation and insulin receptor internalization,” Journal of Biological Chemistry, vol. 271, no. 46, pp. 29489–29496, 1996.
[19]
J. F. A. Swisher, U. Khatri, and G. M. Feldman, “Annexin A2 is a soluble mediator of macrophage activation,” Journal of Leukocyte Biology, vol. 82, no. 5, pp. 1174–1184, 2007.
[20]
L. A. Borthwick, J. Mcgaw, G. Conner et al., “The formation of the cAMP/protein kinase A-dependent annexin 2-S100A10 complex with cystic fibrosis conductance regulator protein (CFTR) regulates CFTR channel function,” Molecular Biology of the Cell, vol. 18, no. 9, pp. 3388–3397, 2007.
[21]
F. H. C. Tsao, K. C. Meyer, X. Chen, N. S. Rosenthal, and J. Hu, “Degradation of annexin I in bronchoalveolar lavage fluid from patients with cystic fibrosis,” American Journal of Respiratory Cell and Molecular Biology, vol. 18, no. 1, pp. 120–128, 1998.
[22]
T. Masaki, M. Tokuda, M. Ohnishi et al., “Enhanced expression of the protein kinase substrate annexin I in human hepatocellular carcinoma,” Hepatology, vol. 24, no. 1, pp. 72–81, 1996.
[23]
H. S. Mohammad, K. Kurokohchi, H. Yoneyama et al., “Annexin A2 expression and phosphorylation are up-regulated in hepatocellular carcinoma,” International Journal of Oncology, vol. 33, no. 6, pp. 1157–1163, 2008.
[24]
C. P. Paweletz, D. K. Ornstein, M. J. Roth et al., “Loss of annexin 1 correlates with early onset of tumorigenesis in esophageal and prostate carcinoma,” Cancer Research, vol. 60, no. 22, pp. 6293–6297, 2000.
[25]
Y. Shiozawa, A. M. Havens, Y. Jung et al., “Annexin II/annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer,” Journal of Cellular Biochemistry, vol. 105, no. 2, pp. 370–380, 2008.
[26]
W. Xin, D. R. Rhodes, C. Ingold, A. M. Chinnaiyan, and M. A. Rubin, “Dysregulation of the annexin family protein family is associated with prostate cancer progression,” American Journal of Pathology, vol. 162, no. 1, pp. 255–261, 2003.
[27]
X.-F. Bai, X.-G. Ni, P. Zhao et al., “Overexpression of annexin 1 in pancreatic cancer and its clinical significance,” World Journal of Gastroenterology, vol. 10, no. 10, pp. 1466–1470, 2004.
[28]
E. Ortiz-Zapater, S. Peiró, O. Roda et al., “Tissue plasminogen activator induces pancreatic cancer cell proliferation by a non-catalytic mechanism that requires extracellular signal-regulated kinase 1/2 activation through epidermal growth factor receptor and annexin A2,” American Journal of Pathology, vol. 170, no. 5, pp. 1573–1584, 2007.
[29]
M. R. Sharma, L. Koltowski, R. T. Ownbey, G. P. Tuszynski, and M. C. Sharma, “Angiogenesis-associated protein annexin II in breast cancer: selective expression in invasive breast cancer and contribution to tumor invasion and progression,” Experimental and Molecular Pathology, vol. 81, no. 2, pp. 146–156, 2006.
[30]
D. Shen, H. R. Chang, Z. Chen et al., “Loss of annexin A1 expression in human breast cancer detected by multiple high-throughput analyses,” Biochemical and Biophysical Research Communications, vol. 326, no. 1, pp. 218–227, 2004.
[31]
D. Shen, F. Nooraie, Y. Elshimali et al., “Decreased expression of annexin A1 is correlated with breast cancer development and progression as determined by a tissue microarray analysis,” Human Pathology, vol. 37, no. 12, pp. 1583–1591, 2006.
[32]
T. Domoto, Y. Miyama, H. Suzuki et al., “Evaluation of S100A10, annexin II and B-FABP expression as markers for renal cell carcinoma,” Cancer Science, vol. 98, no. 1, pp. 77–82, 2007.
[33]
E. Solito, A. Kamal, F. Russo-Marie, J. C. Buckingham, S. Marullo, and M. Perretti, “A novel calcium-dependent proapoptotic effect of annexin 1 on human neutrophils,” The FASEB journal, vol. 17, no. 11, pp. 1544–1546, 2003.
[34]
P.-Y. Tsai, S.-M. Ka, T.-K. Chao et al., “Antroquinonol reduces oxidative stress by enhancing the Nrf2 signaling pathway and inhibits inflammation and sclerosis in focal segmental glomerulosclerosis mice,” Free Radical Biology and Medicine, vol. 50, no. 11, pp. 1503–1516, 2011.
[35]
A. Chen, L.-F. Sheu, Y.-S. Ho et al., “Experimental focal segmental glomerulosclerosis in mice,” Nephron, vol. 78, no. 4, pp. 440–452, 1998.
[36]
S. Romundstad, J. Holmen, K. Kvenild, H. Hallan, and H. Ellekj？r, “Microalbuminuria and all-cause mortality in 2,089 apparently healthy individuals: a 4.4-year follow-up study. The Nord-Tr？ndelag Health Study (HUNT), Norway,” American Journal of Kidney Diseases, vol. 42, no. 3, pp. 466–473, 2003.
[37]
Expert Committee on the Diagnosis Clasification of Diabetes Mellitus, “American diabetes association: clinical practice recommendations,” Diabetes Care, vol. 25, supplement 1, pp. 1–147, 2002.
[38]
H.-A. Shui, S.-M. Ka, S.-M. Yang, Y.-F. Lin, Y.-F. Lo, and A. Chen, “Osteopontin as an injury marker expressing in epithelial hyperplasia lesions helpful in prognosis of focal segmental glomerulosclerosis,” Translational Research, vol. 150, no. 4, pp. 216–222, 2007.
[39]
F. Yu, L.-H. Wu, Y. Tan et al., “Tubulointerstitial lesions of patients with lupus nephritis classified by the 2003 international society of nephrology and renal pathology society system,” Kidney International, vol. 77, no. 9, pp. 820–829, 2010.
[40]
C.-W. Cheng, S.-M. Ka, S.-M. Yang et al., “Nephronectin expression in nephrotoxic acute tubular necrosis,” Nephrology Dialysis Transplantation, vol. 23, no. 1, pp. 101–109, 2008.
[41]
H. Y. Lan, X. Q. Yu, N. Yang et al., “De novo glomerular osteopontin expression in rat crescentic glomerulonephritis,” Kidney International, vol. 53, no. 1, pp. 136–145, 1998.
[42]
G. B. Fogazzi, L. Saglimbeni, G. Banfi et al., “Urinary sediment features in proliferative and non-proliferative glomerular diseases,” Journal of Nephrology, vol. 18, no. 6, pp. 703–710, 2005.
[43]
R. Minutolo, M. M. Balletta, F. Catapano et al., “Mesangial hypercellularity predicts antiproteinuric response to dual blockade of RAS in primary glomerulonephritis,” Kidney International, vol. 70, no. 6, pp. 1170–1176, 2006.
[44]
H. Jiang, G. Guan, R. Zhang et al., “Increased urinary excretion of orosomucoid is a risk predictor of diabetic nephropathy,” Nephrology, vol. 14, no. 3, pp. 332–337, 2009.
[45]
L. Vong, F. D'Acquisto, M. Pederzoli-Ribeil et al., “Annexin 1 cleavage in activated neutrophils: a pivotal role for proteinase 3,” Journal of Biological Chemistry, vol. 282, no. 41, pp. 29998–30004, 2007.
[46]
M. Scannell, M. B. Flanagan, A. DeStefani et al., “Annexin-1 and peptide derivatives are released by apoptotic cells and stimulate phagocytosis of apoptotic neutrophils by macrophages,” Journal of Immunology, vol. 178, no. 7, pp. 4595–4605, 2007.
[47]
M. L. Caramori, P. Fioretto, and M. Mauer, “The need for early predictors of diabetic nephropathy risk: is albumin excretion rate sufficient?” Diabetes, vol. 49, no. 9, pp. 1399–1408, 2000.
[48]
B. P. Tabaei, A. S. Al-Kassab, L. L. Ilag, C. M. Zawacki, and W. H. Herman, “Does microalbuminuria predict diabetic nephropathy?” Diabetes Care, vol. 24, no. 9, pp. 1560–1566, 2001.
[49]
A. Markoff and V. Gerke, “Expression and functions of annexins in the kidney,” American Journal of Physiology: Renal Physiology, vol. 289, no. 5, pp. F949–F956, 2005.
[50]
S. Radke, J. Austermann, F. Russo-Marie, V. Gerke, and U. Rescher, “Specific association of annexin 1 with plasma membrane-resident and internalized EGF receptors mediated through the protein core domain,” The FEBS Letters, vol. 578, no. 1-2, pp. 95–98, 2004.
[51]
Y. S. Kim, J. Ko, I. S. Kim et al., “PKCδ-dependent cleavage and nuclear translocation of annexin A1 by phorbol 12-myristate 13-acetate,” European Journal of Biochemistry, vol. 270, no. 20, pp. 4089–4094, 2003.
[52]
C.-Y. Lin, Y.-M. Jeng, H.-Y. Chou et al., “Nuclear localization of annexin A1 is a prognostic factor in oral squamous cell carcinoma,” Journal of Surgical Oncology, vol. 97, no. 6, pp. 544–550, 2008.
[53]
D. M. Silverstein, “Inflammation in chronic kidney disease:role in the progression of renal and cardiovascular disease,” Pediatric Nephrology, vol. 24, no. 8, pp. 1445–1452, 2009.
[54]
S. B. Kim, W. S. Yang, S. O. Lee, K. P. Lee, J. S. Park, and D. S. Na, “Lipocortin-1 inhibits proliferation of cultured human mesangial cells,” Nephron, vol. 74, no. 1, pp. 39–44, 1996.
[55]
L. C. Alldridge and C. E. Bryant, “Annexin 1 regulates cell proliferation by disruption of cell morphology and inhibition of cyclin D1 expression through sustained activation of the ERK1/2 MAPK signal,” Experimental Cell Research, vol. 290, no. 1, pp. 93–107, 2003.
[56]
Y. Huang, Y. Jin, C.-H. Yan et al., “Involvement of Annexin A2 in p53 induced apoptosis in lung cancer,” Molecular and Cellular Biochemistry, vol. 309, no. 1-2, pp. 117–123, 2008.
[57]
S. Chuthapisith, B. E. Bean, G. Cowley et al., “Annexins in human breast cancer: possible predictors of pathological response to neoadjuvant chemotherapy,” European Journal of Cancer, vol. 45, no. 7, pp. 1274–1281, 2009.
[58]
M. Perretti and E. Solito, “Annexin 1 and neutrophil apoptosis,” Biochemical Society Transactions, vol. 32, no. 3, pp. 507–510, 2004.
[59]
M. La, M. D'Amico, S. Bandiera et al., “Annexin 1 peptides protect against experimental myocardial ischemia-reperfusion: analysis of their mechanism of action,” The FASEB Journal, vol. 15, no. 12, pp. 2247–2256, 2001.
[60]
Y. Yang, P. Hutchinson, and E. F. Morand, “Inhibitory effect of annexin I on synovial inflammation in rat adjuvant arthritis,” Arthritis & Rheumatism, vol. 42, pp. 1538–1544, 1999.
[61]
X. Fan, S. Krahling, D. Smith, P. Williamson, and R. A. Schlegel, “Macrophage surface expression of annexins I and II in the phagocytosis of apoptotic lymphocytes,” Molecular Biology of the Cell, vol. 15, no. 6, pp. 2863–2872, 2004.
[62]
S. McArthur, S. Yazid, H. Christian et al., “Annexin A1 regulates hormone exocytosis through a mechanism involving actin reorganization,” The FASEB Journal, vol. 23, no. 11, pp. 4000–4010, 2009.
[63]
R. L. Sim？es and I. M. Fierro, “Involvement of the Rho-kinase/myosin light chain kinase pathway on human monocyte chemotaxis induced by ATL-1, an aspirin-triggered lipoxin A4 synthetic analog,” Journal of Immunology, vol. 175, no. 3, pp. 1843–1850, 2005.
[64]
K. Nagatoya, T. Moriyama, N. Kawada et al., “Y-27632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction,” Kidney International, vol. 61, no. 5, pp. 1684–1695, 2002.
[65]
T. Nishikimi and H. Matsuoka, “Molecular mechanisms and therapeutic strategies of chronic renal injury: renoprotective effect of rho-kinase inhibitor in hypertensive glomerulosclerosis,” Journal of Pharmacological Sciences, vol. 100, no. 1, pp. 22–28, 2006.
