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Chimenz R, Chirico V, Basile P, et al. HMGB-1 and TGFβ-1 highlight immuno-inflammatory and fibrotic processes before proteinuria onset in pediatric patients with Alport syndrome. J Nephrol. 2021;34(6):1915-1924doi: 10.1007/s40620-021-01015-z.
Chimenz, R., Chirico, V., Basile, P., Carcione, A., Conti, G., Monardo, P., & Lacquaniti, A. (2021). HMGB-1 and TGFβ-1 highlight immuno-inflammatory and fibrotic processes before proteinuria onset in pediatric patients with Alport syndrome. Journal of nephrology, 34(6), 1915-1924. https://doi.org/10.1007/s40620-021-01015-z
Chimenz, R, et al. "HMGB-1 and TGFβ-1 highlight immuno-inflammatory and fibrotic processes before proteinuria onset in pediatric patients with Alport syndrome." Journal of nephrology vol. 34,6 (2021): 1915-1924. doi: https://doi.org/10.1007/s40620-021-01015-z
Chimenz R, Chirico V, Basile P, Carcione A, Conti G, Monardo P, Lacquaniti A. HMGB-1 and TGFβ-1 highlight immuno-inflammatory and fibrotic processes before proteinuria onset in pediatric patients with Alport syndrome. J Nephrol. 2021 Dec;34(6):1915-1924. doi: 10.1007/s40620-021-01015-z. Epub 2021 Mar 24. PMID: 33761123.
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J Nephrol. 2021 Dec;34(6):1915-1924. doi: 10.1007/s40620-021-01015-z. Epub 2021 Mar 24.

HMGB-1 and TGFβ-1 highlight immuno-inflammatory and fibrotic processes before proteinuria onset in pediatric patients with Alport syndrome.

Journal of nephrology

R Chimenz, V Chirico, P Basile, A Carcione, G Conti, P Monardo, A Lacquaniti

Affiliations

  1. Pediatric Nephrology and Dialysis Unit, University Hospital "G. Martino", Messina, Italy. [email protected].
  2. Pediatric Nephrology and Dialysis Unit, University Hospital "G. Martino", Messina, Italy.
  3. Nephrology and Dialysis Unit, Papardo Hospital, Messina, Italy.

PMID: 33761123 DOI: 10.1007/s40620-021-01015-z

Abstract

INTRODUCTION: Alport syndrome (ALP) is a rare genetic condition characterized by progressive involvement of the basal membranes and renal dysfunction. The purpose of the study was to evaluate urinary (u) and serum (s) levels of tumor growth factor (TGF)-beta(β) and high mobility group box (HMGB)-1 in ALP patients with normal renal function, albuminuria and proteinuria.

METHODS: A prospective, single-center study was performed with a follow-up period of 12 months, enrolling 11 pediatric ALP patients and 10 healthy subjects (HS). Normal values of serum creatinine, albuminuria and proteinuria, as well as unaltered estimated glomerular filtration rate (eGFR) were required at enrollment.

RESULTS: ALP patients had significantly higher levels of serum and urinary HMGB1 compared to HS. The same trend was observed for TGF-β1, with higher values in ALP patients than in HS. HMGB1 and TGF-β1 correlated with each other and with markers of renal function and damage. Urinary biomarkers did not correlate with eGFR, whereas sHMGB1 and sTGF-β1 were negatively related to filtration rate (r: - 0.66; p = 0.02, r: - 0.96; p < 0.0001, respectively). Using proteinuria as a dependent variable in a multiple regression model, only the association with sTGF-β1 (β = 0.91, p < 0.0001) remained significant.

CONCLUSIONS: High levels of HMGB1 and TGF-β1 characterized ALP patients with normal renal function, highlighting the subclinical pro-fibrotic and inflammatory mechanisms triggered before the onset of proteinuria. Further studies are needed to evaluate the role of HMGB1 and TGFβ-1 in ALP patients.

© 2021. Italian Society of Nephrology.

Keywords: Alport syndrome; HMGB-1; Proteinuria; Renal biomarker; Renal fibrosis; TGF-β1

References

  1. Bruni V, Petrisano M, Tarsitano F, Falvo F, Parisi F, Cucinotta U et al (2019) “Focus on pediatric nephrology” Alport’s syndrome. J Biol Regul Homeost Agents 33:19–24 - PubMed
  2. Chimenz R (2019) Introduction to the special issue: “Focus on pediatric nephrology.” J Biol Regul Homeost Agents 33:1 - PubMed
  3. Nozu K, Minamikawa S, Yamada S, Oka M, Yanagita M, Morisada N et al (2017) Characterization of contiguous gene deletions in COL4A6 and COL4A5 in Alport syndrome-diffuse leiomyomatosis. J Hum Genet 62:733–735 - PubMed
  4. Meloni I, Muscettola M, Raynaud M, Longo I, Bruttini M, Moizard MP et al (2002) FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation. Nat Genet 30:436–440 - PubMed
  5. Proesmans W, Van Dyck M (2004) Enalapril in children with Alport syndrome. Pediatr Nephrol 19:271–275 - PubMed
  6. Webb NJ, Lam C, Shahinfar S (2011) Efficacy and safety of losartan in children with Alport syndrome—results from a subgroup analysis of prospective, randomized, placebo- or amlodipine-controlled trial. Nephrol Dial Transplant 26:2521–2526 - PubMed
  7. Giani M, Mastrangelo A, Villa R, Turolo S, Marra G, Tirelli AS et al (2013) Alport syndrome: the effects of spironolactone on proteinuria and urinary TGF-β1. Pediatr Nephrol 28:1837–1842 - PubMed
  8. Daina E, Cravedi P, Alpa M, Roccatello D, Gamba S, Perna A et al (2015) A multidrug, antiproteinuric approach to Alport syndrome: a ten-year cohort study. Nephron 130:13–20 - PubMed
  9. Mallett A, Tang W, Clayton PA, Stevenson S, McDonald SP, Hawley CM et al (2014) End-stage kidney disease due to Alport syndrome: outcomes in 296 consecutive Australia and New Zealand Dialysis and Transplant Registry cases. Nephrol Dial Transplant 29:2277–2286 - PubMed
  10. Shang S, Peng F, Wang T, Wu X, Li P, Li Q et al (2019) Genotype–phenotype correlation and prognostic impact in Chinese patients with Alport syndrome. Mol Genet Genom Med. 29:e741 - PubMed
  11. Levey AS, Cattran D, Friedman A, Miller WG, Sedor J, Tuttle K et al (2009) Proteinuria as a surrogate outcome in CKD: report of a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis 54:205–226 - PubMed
  12. Devarajan P (2010) The use of targeted biomarkers for chronic kidney disease. Adv Chronic Kidney Dis 17:469–479 - PubMed
  13. Schnaper HW (2014) Remnant nephron physiology and the progression of chronic kidney disease. Pediatr Nephrol 29:193–202 - PubMed
  14. Sayers R, Kalluri R, Rogers KD, Shiel CF, Meehan DT, Cosgrove D (1999) Role for transforming growth factor-beta1 in Alport renal disease progression. Kidney Int 56:1662–1673 - PubMed
  15. Goumenos DS, Tsakas S, El Nahas AM, Alexandri S, Oldroyd S, Kalliakmani P et al (2002) Transforming growth factor-β1 in the kidney and urine of patients with glomerular disease and proteinuria. Nephrol Dial Transplant 17:2145–2152 - PubMed
  16. den Haan JMM, Kraal G, Bevan MJ (2007) Cutting edge: lipopolysaccharide induces IL-10-producing regulatory CD4+ T cells that suppress the CD8+ T cell response. J Immunol 178:5429–5433 - PubMed
  17. Chirico V, Lacquaniti A, Salpietro V, Munafò C, Calabrò MP, Buemi M et al (2014) High-mobility group box 1 (HMGB1) in childhood: from bench to bedside. Eur J Pediatr 173:1123–1136 - PubMed
  18. Arrigo T, Chirico V, Salpietro V, Munafò C, Ferraù V, Gitto E et al (2013) High-mobility group protein B1: a new biomarker of metabolic syndrome in obese children. Eur J Endocrinol 168:631–638 - PubMed
  19. Chimenz R, Lacquaniti A, Colavita L, Chirico V, Fede C, Buemi M et al (2016) High mobility group box 1 and tumor growth factor β: useful biomarkers in pediatric patients receiving peritoneal dialysis. Ren Fail 38:1370–1376 - PubMed
  20. Bianchi ME, Manfredi AA (2007) High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev 220:35–46 - PubMed
  21. Wu H, Ma J, Wang P (2010) HMGB1 contributes to kidney ischemia reperfusion injury. J Am Soc Nephrol 21:1878–1890 - PubMed
  22. Rademacher ER, Sinaiko AR (2009) Albuminuria in children. Curr Opin Nephrol Hypertens 18:246–251 - PubMed
  23. Abulaban KM, Song H, Zhang X et al (2016) Predicting decline of kidney function in lupus nephritis using urine biomarkers. Lupus 25:1012–1018 - PubMed
  24. Zickert A, Palmblad K, Sundelin B, Chavan S, Tracey KJ, Bruchfeld A et al (2012) Renal expression and serum levels of high mobility group box 1 protein in lupus nephritis. Arthritis Res Ther 14:R36 - PubMed
  25. de Souza AW, Abdulahad WH, Sosicka P, Bijzet J, Limburg PC, Stegeman CA et al (2014) Are urinary levels of high mobility group box 1 markers of active nephritis in anti-neutrophil cytoplasmic antibody-associated vasculitis? Clin Exp Immunol 178:270–278 - PubMed
  26. Woroniecki RP, Shatat IF, Supe K, Du Z, Kaskel FJ (2008) Urinary cytokines and steroid responsiveness in idiopathic nephrotic syndrome of childhood. Am J Nephrol 28:83–90 - PubMed
  27. Zieg J, Blahova K, Seeman T, Bronsky J, Dvorakova H, Pechova M et al (2011) Urinary transforming growth factor-beta1 in children with obstructive uropathy. Nephrology 16:595–598 - PubMed
  28. Wong MG, Perkovic V, Woodward M, Chalmers J, Li Q, Hillis GS et al (2013) Circulating bone morphogenetic protein-7 and transforming growth factor-beta1 are better predictors of renal end points in patients with type 2 diabetes mellitus. Kidney Int 83:278–284 - PubMed
  29. Gross O, Beirowski B, Koepke ML, Kuck J, Reiner M, Addicks K et al (2003) Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int 63:438–446 - PubMed
  30. Gross O, Perin L, Deltas C (2014) Alport syndrome from bench to bedside: the potential of current treatment beyond RAAS blockade and the horizon of future therapies. Nephrol Dial Transplant 29:iv124–iv130 - PubMed
  31. Chen W, Tang D, Dai Y, Diao H (2019) Establishment of microRNA, transcript and protein regulatory networks in Alport syndrome induced pluripotent stem cells. Mol Med Rep 19:238–250 - PubMed
  32. Tang SCW, Yiu WH (2020) Innate immunity in diabetic kidney disease. Nat Rev Nephrol 16:206–222 - PubMed
  33. Mudaliar H, Pollock C, Komala MG, Chadban S, Wu HL, Panchapakesan U et al (2013) The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules. Am J Physiol Ren Physiol 305:F143–F154 - PubMed
  34. Tian S, Zhang L, Tang J, Guo X, Dong K, Chen SY (2015) HMGB1 exacerbates renal tubulointerstitial fibrosis through facilitating M1 macrophage phenotype at the early stage of obstructive injury. Am J Physiol Ren Physiol 308:F69–F75 - PubMed
  35. Chirico V, Lacquaniti A, Leonardi S, Grasso L, Rotolo N, Romano C et al (2015) Acute pulmonary exacerbation and lung function decline in patients with cystic fibrosis: high-mobility group box 1 (HMGB1) between inflammation and infection. Clin Microbiol Infect 21:368.e1–9 - PubMed
  36. Rabadi MM, Ghaly T, Goligorksy MS, Ratliff BB (2012) HMGB1 in renal ischemic injury. Am J Physiol Renal Physiol 303:F873–F885 - PubMed
  37. Abdulahad DA, Westra J, Bijzet J, Dolff S, van Dijk MC, Limburg PC et al (2012) Urine levels of HMGB1 in systemic lupus erythematosus patients with and without renal manifestations. Arthritis Res Ther 14:R184 - PubMed
  38. Hayashida T, Wu MH, Pierce A, Poncelet AC, Varga J, Schnaper HW (2007) MAP-kinase activity necessary for TGFbeta1-stimulated mesangial cell type I collagen expression requires adhesion dependent phosphorylation of FAK tyrosine 397. J Cell Sci 120:4230–4240 - PubMed
  39. Ortega-Velazquez R, Gonzalez-Rubio M, Ruiz-Torres MP, Diez-Marques ML, Iglesias MC, Rodriguez-Puyol M et al (2004) Collagen I upregulates extracellular matrix gene expression and secretion of TGF-beta 1 by cultured human mesangial cells. Am J Physiol Cell Physiol 286:C1335–C1343 - PubMed
  40. Hahm K, Lukashev ME, Luo Y, Yang WJ, Dolinski BM, Weinreb PH et al (2007) Alphav beta6 integrin regulates renal fibrosis and inflammation in Alport mouse. Am J Pathol 170:110–125 - PubMed
  41. Bruchfeld A, Qureshi AR, Lindholm B, Barany P, Yang L, Stenvinkel P, Tracey KJ (2008) High mobility group box protein-1 correlates with renal function in chronic kidney disease (CKD). Mol Med 14:109–115 - PubMed

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