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Journal of Clinical Immunology

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01-02-2014 | Original Research

C3a, C5a Renal Expression and Their Receptors are Correlated to Severity of IgA Nephropathy

Authors: Lu Liu, Ying Zhang, Ximei Duan, Qi Peng, Quan Liu, Yali Zhou, Songxia Quan, Guolan Xing

Published in: Journal of Clinical Immunology | Issue 2/2014

Abstract

Background

IgA nephropathy (IgAN) is the most common primary kidney disease, often leading to chronic renal failure. Complement activation products C3a and C5a have broad pro-inflammatory potential through their receptors, C3aR and C5aR, and contribute to the pathogenesis of several inflammatory and autoimmune diseases, but their roles in IgAN are poorly defined.

Purpose

This study aimed to establish correlations between renal C3a, C5a, C3aR, C5aR, or serum/urinary C3a, C5a with clinical features and renal histopathology in patients with IgAN.

Methods

Eighty-three patients with renal biopsy proven IgAN were investigated. Thirty patients fulfilled Haas’s II, 30 fulfilled Haas’s III and 23 fulfilled Haas’s IV criteria. Deposition of C3a and C5a was assessed by immunohistochemistry. C3aR and C5aR mRNAs and proteins in kidney tissue were examined by real-time quantitative PCR (RT-qPCR) and immunohistochemical staining, respectively. C3a and C5a levels were quantified by ELISA in serum and urine samples of 30 IgAN patients, 10 control subjects and 10 septic patients.

Results

Renal C3a and C5a deposition and C3aR and C5aR expression increased with increasing grades of renal pathology in IgAN patients. They positively correlated with proteinuria and serum creatinine (SCr), but not serum C-reactive protein (CRP) or complement 3 (C3). Serum C3a and C5a increased to levels comparable to septic patients but did not differ among IgAN sub-groups. In contrast, urinary C3a and C5a increased significantly and correlated positively with renal pathological grades.

Conclusions

In patients with IgAN, urinary and renal C3a and C5a and renal expression of C3aR and C5aR are significantly correlated with the activity and severity of renal injury. This observation warrants further study into the roles of C3a, C5a and their receptors in the pathogenesis of IgAN and as potential therapeutic targets.

Berthoux FC, Mohey H, Afiani A. Natural history of primary IgA nephropathy. Semin Nephrol. 2008;28(1):4–9.PubMedCrossRef

Moldoveanu Z, Wyatt RJ, Lee JY, Tomana M, Julian BA, Mestecky J, et al. Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels. Kidney Int. 2007;71(11):1148–54.PubMedCrossRef

Gharavi AG, Moldoveanu Z, Wyatt RJ, Barker CV, Woodford SY, Lifton RP, et al. Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. J Am Soc Nephrol. 2008;19(5):1008–14.PubMedCentralPubMedCrossRef

Suzuki K, Honda K, Tanabe K, Toma H, Nihei H, Yamaguchi Y. Incidence of latent mesangial IgA deposition in renal allograft donors in Japan. Kidney Int. 2003;63(6):2286–94.PubMedCrossRef

Endo M, Ohi H, Ohsawa I, Fujita T, Matsushita M. Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy. Nephrol Dial Transplant. 1998;13(8):1984–90.PubMedCrossRef

Roos A, Rastaldi MP, Calvaresi N, Oortwijn BD, Schlagwein N, van Gijlswijk-Janssen DJ, et al. Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease. J Am Soc Nephrol. 2006;17(6):1724–34.PubMedCrossRef

Espinosa M, Ortega R, Gomez-Carrasco JM, Lopez-Rubio F, Lopez-Andreu M, Lopez-Oliva MO, et al. Mesangial C4d deposition: a new prognostic factor in IgA nephropathy. Nephrol Dial Transplant. 2009;24(3):886–91.PubMedCrossRef

Ohsawa I, Ishii M, Ohi H, Tomino Y. Pathological scenario with the mannose-binding lectin in patients with IgA nephropathy. J Biomed Biotechnol. 2012;2012:476739.PubMedCentralPubMedCrossRef

Gharavi AG, Kiryluk K, Choi M, Li Y, Hou P, Xie J, et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet. 2011;43(4):321–7.PubMedCentralPubMedCrossRef

10.

Peng Q, Li K, Sacks SH, Zhou W. The role of anaphylatoxins C3a and C5a in regulating innate and adaptive immune responses. Inflamm Allergy Drug Targets. 2009;8(3):236–46.PubMedCrossRef

11.

Mizuno M, Blanchin S, Gasque P, Nishikawa K, Matsuo S. High levels of complement C3a receptor in the glomeruli in lupus nephritis. Am J Kidney Dis. 2007;49(5):598–606.PubMedCrossRef

12.

Bao L, Osawe I, Haas M, Quigg RJ. Signaling through up-regulated C3a receptor is key to the development of experimental lupus nephritis. J Immunol. 2005;175(3):1947–55.PubMed

13.

Gueler F, Rong S, Gwinner W, Mengel M, Brocker V, Schon S, et al. Complement 5a receptor inhibition improves renal allograft survival. J Am Soc Nephrol. 2008;19(12):2302–12.PubMedCentralPubMedCrossRef

14.

Li Q, Peng Q, Xing G, Li K, Wang N, Farrar CA, et al. Deficiency of C5aR prolongs renal allograft survival. J Am Soc Nephrol. 2010;21(8):1344–53.PubMedCentralPubMedCrossRef

15.

Thurman JM, Lenderink AM, Royer PA, Coleman KE, Zhou J, Lambris JD, et al. C3a is required for the production of CXC chemokines by tubular epithelial cells after renal ishemia/reperfusion. J Immunol. 2007;178(3):1819–28.PubMed

16.

Peng Q, Li K, Smyth LA, Xing G, Wang N, Meader L, et al. C3a and C5a promote renal ischemia-reperfusion injury. J Am Soc Nephrol. 2012;23(9):1474–85.PubMedCentralPubMedCrossRef

17.

Abou-Ragheb HH, Williams AJ, Brown CB, Milford-Ward A. Plasma levels of the anaphylatoxins C3a and C4a in patients with IgA nephropathy/Henoch-Schonlein nephritis. Nephron. 1992;62(1):22–6.PubMedCrossRef

18.

Janssen U, Bahlmann F, Kohl J, Zwirner J, Haubitz M, Floege J. Activation of the acute phase response and complement C3 in patients with IgA nephropathy. Am J Kidney Dis. 2000;35(1):21–8.PubMedCrossRef

19.

Abe K, Miyazaki M, Koji T, Furusu A, Nakamura-Kurashige T, Nishino T, et al. Enhanced expression of complement C5a receptor mRNA in human diseased kidney assessed by in situ hybridization. Kidney Int. 2001;60(1):137–46.PubMedCrossRef

20.

Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Kohl J. The role of the anaphylatoxins in health and disease. Mol Immunol. 2009;46(14):2753–66.PubMedCentralPubMedCrossRef

21.

Haas M. Histologic subclassification of IgA nephropathy: a clinicopathologic study of 244 cases. Am J Kidney Dis. 1997;29(6):829–42.PubMedCrossRef

22.

Matthews KW, Mueller-Ortiz SL, Wetsel RA. Carboxypeptidase N: a pleiotropic regulator of inflammation. Mol Immunol. 2004;40(11):785–93.PubMedCrossRef

23.

Leung LL, Myles T, Nishimura T, Song JJ, Robinson WH. Regulation of tissue inflammation by thrombin-activatable carboxypeptidase B (or TAFI). Mol Immunol. 2008;45(16):4080–3.PubMedCentralPubMedCrossRef

24.

Sayah S, Jauneau AC, Patte C, Tonon MC, Vaudry H, Fontaine M. Two different transduction pathways are activated by C3a and C5a anaphylatoxins on astrocytes. Brain Res Mol Brain Res. 2003;112(1–2):53–60.PubMedCrossRef

25.

Onda K, Ohsawa I, Ohi H, Tamano M, Mano S, Wakabayashi M, et al. Excretion of complement proteins and its activation marker C5b-9 in IgA nephropathy in relation to renal function. BMC Nephrol. 2011;12:64.PubMedCentralPubMedCrossRef

Title: C3a, C5a Renal Expression and Their Receptors are Correlated to Severity of IgA Nephropathy
Authors: Lu Liu
Ying Zhang
Ximei Duan
Qi Peng
Quan Liu
Yali Zhou
Songxia Quan
Guolan Xing
Publication date: 01-02-2014
Publisher: Springer US
Published in: Journal of Clinical Immunology / Issue 2/2014
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-013-9970-6

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C3a, C5a Renal Expression and Their Receptors are Correlated to Severity of IgA Nephropathy

Abstract

Background

Purpose

Methods

Results

Conclusions

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Abstract

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Results

Conclusions

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