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Urinary fibrogenic cytokines ET-1 and TGF-β1 are associated with urinary angiotensinogen levels in obese children

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Abstract

Background

Fibrogenic cytokines are recognized as putative drivers of disease activity and histopathological deterioration in various kidney diseases. We compared urinary transforming growth factor β1 (U-TGF-β1) and endothelin 1 (U-ET-1) levels across body mass index classes and assessed their association with the level of urinary angiotensinogen (U-AGT), a biomarker of intrarenal renin–angiotensin–aldosterone system (RAAS).

Methods

The was a cross-sectional evaluation of 302 children aged 8–9 years. Ambulatory blood pressure (BP), insulin resistance (HOMA-IR), aldosterone level and renal function were evaluated. U-ET-1, U-TGF-β1 and U-AGT levels were determined by immunoenzymatic methods.

Results

Obese children presented with the lowest levels of U-ET-1 and U-TGF-β1, but the difference was only significant for U-ET-1. In obese children, the median levels of both U-ET-1 and U-TGF-β1 tended to increase across tertiles (T1–T3) of U-AGT (U-ET-1: T1, 19.9 (14.2–26.3); T2, 32.5 (23.3–141.6); T3, 24.8 (18.7–51.5) ng/g creatinine, p = 0.007; U-TGF-β1: T1, 2.2 (1.8–4.0); T2, 4.3 (2.7–11.7); T3, 4.9 (3.8–10.1) ng/g creatinine, p = 0.004]. In multivariate models, in the obese group, U-ET-1 was associated with HOMA-IR and aldosterone and U-AGT levels, and U-TGF-β1 was associated with U-AGT levels and 24 h-systolic BP.

Conclusions

Whereas the initial hypothesis of higher levels of urinary fibrogenic cytokines in obese children was not confirmed in our study, both TGF-β1 and U-ET-1 levels were associated with U-AGT level, which likely reflects an early interplay between tissue remodeling and RAAS in obesity-related kidney injury.

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References

  1. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, Abu-Rmeileh NME, Achoki T, AlBuhairan FS, Alemu ZA, Alfonso R, Ali MK, Ali R, Guzman NA, Ammar W, Anwari P, Banerjee A, Barquera S, Basu S, Bennett DA, Bhutta Z, Blore J, Cabral N, Nonato IC, Chang J-C, Chowdhury R, Courville KJ, Criqui MH, Cundiff DK, Dabhadkar KC, Dandona L, Davis A, Dayama A, Dharmaratne SD, Ding EL, Durrani AM, Esteghamati A, Farzadfar F, Fay DFJ, Feigin VL, Flaxman A, Forouzanfar MH, Goto A, Green MA, Gupta R, Hafezi-Nejad N, Hankey GJ, Harewood HC, Havmoeller R, Hay S, Hernandez L, Husseini A, Idrisov BT, Ikeda N, Islami F, Jahangir E, Jassal SK, Jee SH, Jeffreys M, Jonas JB, Kabagambe EK, Khalifa SEAH, Kengne AP, Khader YS, Khang Y-H, Kim D, Kimokoti RW, Kinge JM, Kokubo Y, Kosen S, Kwan G, Lai T, Leinsalu M, Li Y, Liang X, Liu S, Logroscino G, Lotufo PA, Lu Y, Ma J, Mainoo NK, Mensah GA, Merriman TR, Mokdad AH, Moschandreas J, Naghavi M, Naheed A, Nand D, Narayan KMV, Nelson EL, Neuhouser ML, Nisar MI, Ohkubo T, Oti SO, Pedroza A, Prabhakaran D, Roy N, Sampson U, Seo H, Sepanlou SG, Shibuya K, Shiri R, Shiue I, Singh GM, Singh JA, Skirbekk V, Stapelberg NJC, Sturua L, Sykes BL, Tobias M, Tran BX, Trasande L, Toyoshima H, van de Vijver S, Vasankari TJ, Veerman JL, Velasquez-Melendez G, Vlassov VV, Vollset SE, Vos T, Wang C, Wang SX, Weiderpass E, Werdecker A, Wright JL, Yang YC, Yatsuya H, Yoon J, Yoon S-J, Zhao Y, Zhou M, Zhu S, Lopez AD, Murray CJL, Gakidou E (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384:766–781

    Article  PubMed Central  Google Scholar 

  2. Finucane MM, Stevens GA, Cowan MJ, Danaei G, Lin JK, Paciorek CJ, Singh GM, Gutierrez HR, Lu Y, Bahalim AN, Farzadfar F, Riley LM, Ezzati M (2011) National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9 · 1 million participants. Lancet 377:557–567

    Article  PubMed Central  PubMed  Google Scholar 

  3. Wang Y, Chen X, Song Y, Caballero B, Cheskin LJ (2008) Association between obesity and kidney disease: a systematic review and meta-analysis. Kidney Int 73:19–33

    Article  CAS  PubMed  Google Scholar 

  4. Savino A, Pelliccia P, Chiarelli F, Mohn A (2010) Obesity-related renal injury in childhood. Horm Res Paediatr 73:303–311

    Article  CAS  PubMed  Google Scholar 

  5. Kalaitzidis RG, Siamopoulos KC (2011) The role of obesity in kidney disease: recent findings and potential mechanisms. Int Urol Nephrol 43:771–784

    Article  PubMed  Google Scholar 

  6. Chagnac A, Weinstein T, Korzets A, Ramadan E, Hirsch J, Gafter U (2000) Glomerular hemodynamics in severe obesity. Am J Physiol Ren Physiol 278:F817–F822

    CAS  Google Scholar 

  7. Cignarelli M, Lamacchia O (2007) Obesity and kidney disease. Nutr Metab Cardiovasc Dis 17:757–762

    Article  CAS  PubMed  Google Scholar 

  8. Prunotto M, Ghiggeri G, Bruschi M, Gabbiani G, Lescuyer P, Hocher B, Chaykovska L, Berrera M, Moll S (2011) Renal fibrosis and proteomics: current knowledge and still key open questions for proteomic investigation. J Proteomics 74:1855–1870

    Article  CAS  PubMed  Google Scholar 

  9. Hocher B, Thöne-Reineke C, Rohmeiss P, Schmager F, Slowinski T, Burst V, Siegmund F, Quertermous T, Bauer C, Neumayer HH, Schleuning WD, Theuring F (1997) Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension. J Clin Invest 99:1380–1389

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Shindo T, Kurihara H, Maemura K, Kurihara Y, Ueda O, Suzuki H, Kuwaki T, Ju K-H, Wang Y, Ebihara A, Nishimatsu H, Moriyama N, Fukuda M, Akimoto Y, Hirano H, Morita H, Kumada M, Yazaki Y, Nagai R, Kimura K (2002) Renal damage and salt-dependent hypertension in aged transgenic mice overexpressing endothelin-1. J Mol Med 80:105–116

    Article  CAS  PubMed  Google Scholar 

  11. Gordon KJ, Blobe GC (2008) Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta 1782:197–228

    Article  CAS  Google Scholar 

  12. Bottinger EP, Bitzer M (2002) TGF-beta signaling in renal disease. J Am Soc Nephrol 13:2600–2610

    Article  PubMed  Google Scholar 

  13. Janas J, Sitkiewicz D, Januszewicz A, Szczesniak C, Grenda R, Janas RM (2000) Endothelin-1 inactivating peptidase in the human kidney and urine. J Hypertens 18:475–483

    Article  CAS  PubMed  Google Scholar 

  14. Silva AC S e, Valério FC, Vasconcelos MA, Miranda DM, Oliveira EA (2013) Interactions between cytokines, congenital anomalies of kidney and urinary tract and chronic kidney disease. Clin Dev Immunol 2013:597920

    Google Scholar 

  15. Olianti C, Imperiale A, Materassi M, Seracini D, Ienuso R, Tommasi M, Pupi A, La Cava G (2004) Urinary endothelin-1 excretion according to morpho-functional damage lateralization in reflux nephropathy. Nephrol Dial Transplant 19:1774–1778

    Article  CAS  PubMed  Google Scholar 

  16. Grenda R, Wühl E, Litwin M, Janas R, Sladowska J, Arbeiter K, Berg U, Caldas-Afonso A, Fischbach M, Mehls O, Sallay P, Schaefer F, Wuhl E, Litwin M, Janas R, Sladowska J, Arbeiter K, Berg U, Caldas-Afonso A, Fischbach M, Mehls O, Sallay P, Schaefer F, Wühl E, Litwin M, Janas R, Sladowska J, Arbeiter K, Berg U, Caldas-Afonso A, Fischbach M, Mehls O, Sallay P, Schaefer F (2007) Urinary excretion of endothelin-1 (ET-1), transforming growth factor- beta1 (TGF- beta1) and vascular endothelial growth factor (VEGF165) in paediatric chronic kidney diseases: results of the ESCAPE trial. Nephrol Dial Transplant 22:3487–3494

    Article  CAS  PubMed  Google Scholar 

  17. Murakami K, Takemura T, Hino S, Yoshioka K (1997) Urinary transforming growth factor-beta in patients with glomerular diseases. Pediatr Nephrol 11:334–336

    Article  CAS  PubMed  Google Scholar 

  18. Wasilewska A, Zoch-Zwierz W, Taranta-Janusz K (2009) Urinary transforming growth factor beta1 in children and adolescents with congenital solitary kidney. Pediatr Nephrol 24:753–759

    Article  PubMed  Google Scholar 

  19. Barton M, Carmona R, Ortmann J, Krieger JE, Traupe T (2003) Obesity-associated activation of angiotensin and endothelin in the cardiovascular system. Int J Biochem Cell Biol 35:826–837

    Article  CAS  PubMed  Google Scholar 

  20. Barton M, Carmona R, Morawietz H, D’Uscio LV, Goettsch W, Hillen H, Haudenschild CC, Krieger JE, Munter K, Lattmann T, Luscher TF, Shaw S (2000) Obesity is associated with tissue-specific activation of renal angiotensin-converting enzyme in vivo: evidence for a regulatory role of endothelin. Hypertension 35:329–336

    Article  CAS  PubMed  Google Scholar 

  21. Wolf G (2006) Renal injury due to renin-angiotensin-aldosterone system activation of the transforming growth factor-beta pathway. Kidney Int 70:1914–1919

    Article  CAS  PubMed  Google Scholar 

  22. Huang Y, Noble NA, Zhang J, Xu C, Border WA (2007) Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. Kidney Int 72:45–52

    Article  CAS  Google Scholar 

  23. Kobori H, Urushihara M (2013) Augmented intrarenal and urinary angiotensinogen in hypertension and chronic kidney disease. Pflugers Arch 465:3–12

    PubMed Central  CAS  Google Scholar 

  24. Larsen PS, Kamper-Jorgensen M, Adamson A, Barros H, Bonde JP, Brescianini S, Brophy S, Casas M, Charles M-AA, Devereux G, Eggesbo M, Fantini MP, Frey U, Gehring U, Grazuleviciene R, Henriksen TB, Hertz-Picciotto I, Heude B, Hryhorczuk DO, Inskip H, Jaddoe VWV, Lawlor DA, Ludvigsson J, Kelleher C, Kiess W, Koletzko B, Kuehni CE, Kull I, Kyhl HB, Magnus P, Momas I, Murray D, Pekkanen J, Polanska K, Porta D, Poulsen G, Richiardi L, Roeleveld N, Skovgaard AM, Sram RJ, Strandberg-Larsen K, Thijs C, Van Eijsden M, Wright J, Vrijheid M, Andersen A-MNM, Kamper-Jørgensen M, Adamson A, Barros H, Bonde JP, Brescianini S, Brophy S, Casas M, Charles M-AA, Devereux G, Eggesbø M, Fantini MP, Frey U, Gehring U, Grazuleviciene R, Henriksen TB, Hertz-Picciotto I, Heude B, Hryhorczuk DO, Inskip H, Jaddoe VWV, Lawlor DA, Ludvigsson J, Kelleher C, Kiess W, Koletzko B, Kuehni CE, Kull I, Kyhl HB, Magnus P, Momas I, Murray D, Pekkanen J, Polanska K, Porta D, Poulsen G, Richiardi L, Roeleveld N, Skovgaard AM, Sram RJ, Strandberg-Larsen K, Thijs C, Van Eijsden M, Wright J, Vrijheid M, Andersen A-MNM (2013) Pregnancy and birth cohort resources in europe: a large opportunity for aetiological child health research. Paediatr Perinat Epidemiol 27:393–414

    Article  PubMed  Google Scholar 

  25. Durão C, Severo M, Oliveira A, Moreira P, Guerra A, Barros H, Lopes C, Durao C, Severo M, Oliveira A, Moreira P, Guerra A, Barros H, Lopes C (2014) Evaluating the effect of energy-dense foods consumption on preschool children’s body mass index: a prospective analysis from 2 to 4 years of age. Eur J Nutr 54:835–843

    Article  PubMed  Google Scholar 

  26. De Onis M, Onyango AW, Borghi E, Siyam A, Nishida C, Siekmann J (2007) Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ 85:660–667

    Article  PubMed Central  PubMed  Google Scholar 

  27. Flynn JT, Daniels SR, Hayman LL, Maahs DM, McCrindle BW, Mitsnefes M, Zachariah JP, Urbina EM (2014) Update: ambulatory blood pressure monitoring in children and adolescents: a scientific statement from the American Heart Association. Hypertension 63:1116–1135

    Article  PubMed Central  CAS  Google Scholar 

  28. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents (2004) The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 114:555–576

    Article  Google Scholar 

  29. Zappitelli M, Parvex P, Joseph L, Paradis G, Grey V, Lau S, Bell L (2006) Derivation and validation of cystatin C-based prediction equations for GFR in children. Am J Kidney Dis 48:221–230

    Article  CAS  Google Scholar 

  30. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419

    Article  CAS  PubMed  Google Scholar 

  31. Dhaun N, Lilitkarntakul P, Macintyre IM, Muilwijk E, Johnston NR, Kluth DC, Webb DJ, Goddard J (2009) Urinary endothelin-1 in chronic kidney disease and as a marker of disease activity in lupus nephritis. Am J Physiol Ren Physiol 296:F1477–1483

    Article  CAS  Google Scholar 

  32. Marcus Y, Shefer G, Stern N (2013) Adipose tissue renin-angiotensin-aldosterone system (RAAS) and progression of insulin resistance. Mol Cell Endocrinol 378:1–14

    Article  CAS  PubMed  Google Scholar 

  33. Felizardo RJF (2014) Obesity in kidney disease: a heavyweight opponent. World J Nephrol 3:50–63

    Article  PubMed Central  PubMed  Google Scholar 

  34. Hunley TE, Ma L-JJ, Kon V (2010) Scope and mechanisms of obesity-related renal disease. Curr Opin Nephrol Hypertens 19:227–234

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Wong S, Brennan FE, Young MJ, Fuller PJ, Cole TJ (2007) A direct effect of aldosterone on endothelin-1 gene expression in vivo. Endocrinology 148:1511–1517

    Article  CAS  Google Scholar 

  36. Torun D, Ozelsancak R, Turan I, Micozkadioglu H, Sezer S, Ozdemir FN (2007) The relationship between obesity and transforming growth factor beta on renal damage in essential hypertension. Int Heart J 48:733–741

    Article  CAS  Google Scholar 

  37. Glowinska B, Urban M, Hryniewicz A, Peczynska J, Florys B, Al-Hwish M (2004) Endothelin-1 plasma concentration in children and adolescents with atherogenic risk factors. Kardiol Pol 61:329–338

    PubMed  Google Scholar 

  38. Wu Y, Liu Z, Xiang Z, Zeng C, Chen Z, Ma X, Li L (2006) Obesity-related glomerulopathy: insights from gene expression profiles of the glomeruli derived from renal biopsy samples. Endocrinology 147:44–50

    Article  CAS  PubMed  Google Scholar 

  39. Toda N, Nakanishi S, Tanabe S (2013) Aldosterone affects blood flow and vascular tone regulated by endothelium-derived NO: therapeutic implications. Br J Pharmacol 168:519–533

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Sarafidis PA, Ruilope LM (2006) Insulin resistance, hyperinsulinemia, and renal injury: mechanisms and implications. Am J Nephrol 26:232–244

    Article  Google Scholar 

  41. Miyauchi T, Masaki T (1999) Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol 61:391–415

    Article  CAS  PubMed  Google Scholar 

  42. Jin C, Speed JS, Hyndman KA, O’Connor PM, Pollock DM (2013) Sex differences in ET-1 receptor expression and Ca2+ signaling in the IMCD. Am J Physiol Ren Physiol 305:F1099–1104

    Article  CAS  Google Scholar 

  43. Nakano D, Pollock JS, Pollock DM (2008) Renal medullary ETB receptors produce diuresis and natriuresis via NOS1. Am J Physiol Ren Physiol 294:F1205–1211

    Article  CAS  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge the families enrolled in Generation XXI for their kindness, all members of the research team for their enthusiasm and perseverance and the participating hospitals and their staff for their help and support.

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Authors and Affiliations

  1. Epidemiology Research Unit (EPIUnit), Institute of Public Health, University of Porto, Rua das Taipas, nº 135, 4050-600, Porto, Portugal

    Liane Correia-Costa, Dina Cosme, João Tiago Guimarães, Alberto Caldas Afonso & Ana Azevedo

  2. Division of Pediatric Nephrology, Integrated Pediatric Hospital, Centro Hospitalar São João, Porto, Portugal

    Liane Correia-Costa & Alberto Caldas Afonso

  3. Department of Pediatrics, Faculty of Medicine, University of Porto, Porto, Portugal

    Liane Correia-Costa, António Guerra & Alberto Caldas Afonso

  4. Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal

    Manuela Morato, Teresa Sousa, Dina Cosme & António Albino-Teixeira

  5. Center for Drug Discovery and Innovative Medicines (MedInUP), University of Porto, Porto, Portugal

    Manuela Morato, Teresa Sousa & António Albino-Teixeira

  6. Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal

    Manuela Morato

  7. Department of Clinical Pathology, Centro Hospitalar São João, Porto, Portugal

    João Tiago Guimarães

  8. Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal

    João Tiago Guimarães

  9. Division of Pediatric Nutrition, Integrated Pediatric Hospital, Centro Hospitalar São João, Porto, Portugal

    António Guerra

  10. Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany

    Franz Schaefer

  11. Department of Clinical Epidemiology, Predictive Medicine and Public Health, Faculty of Medicine, University of Porto, Porto, Portugal

    Ana Azevedo

Authors
  1. Liane Correia-Costa
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  2. Manuela Morato
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  3. Teresa Sousa
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  4. Dina Cosme
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  5. João Tiago Guimarães
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  6. António Guerra
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  7. Franz Schaefer
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  8. Alberto Caldas Afonso
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  9. Ana Azevedo
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  10. António Albino-Teixeira
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Corresponding author

Correspondence to Liane Correia-Costa.

Ethics declarations

The ObiKid study was approved by the Ethics Committee of Centro Hospitalar São João, E.P.E. and Faculty of Medicine of the University of Porto and complies with the Helsinki Declaration and the current national legislation. Written informed consent from parents (or their legal substitute) and verbal assent from children was obtained, concerning information and biological sample gathering.

Conflicts of interest

None of the authors have any financial or nonfinancial competing interests concerning the present study.

Sources of funding

This project was supported by the Portuguese Foundation for Science and Technology, Lisbon, Portugal (PTDC/DTP-PIC/0239/2012), that granted the funds for study design and data collection and analysis. Liane Correia-Costa was supported by Portuguese Foundation for Science and Technology (grant SFRH/SINTD/95898/2013), Teresa Sousa was supported by a Ciência 2008 Contract, funded by Portuguese Foundation for Science and Technology and POPH/FSE (EC) and Franz Schaefer was supported by the ERA-EDTA Research Programme and the KfH Foundation for Preventive Medicine.

Additional information

Liane Correia-Costa and Manuela Morato contributed equally as first authors to this paper.

Ana Azevedo and António Albino-Teixeira contributed equally to the supervision and scientific revision of this paper.

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Correia-Costa, L., Morato, M., Sousa, T. et al. Urinary fibrogenic cytokines ET-1 and TGF-β1 are associated with urinary angiotensinogen levels in obese children. Pediatr Nephrol 31, 455–464 (2016). https://doi.org/10.1007/s00467-015-3232-1

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