Top

Journal of Nephrology

Published in:

01-06-2020 | Original Article

MicroRNA-21-5p participates in IgA nephropathy by driving T helper cell polarization

Authors: Bo-yang Xu, Si-jun Meng, Su-fang Shi, Li-jun Liu, Ji-cheng Lv, Li Zhu, Hong Zhang

Published in: Journal of Nephrology | Issue 3/2020

Abstract

Background

Previous studies have revealed abnormal lymphocyte subsets in IgA nephropathy (IgAN). Some microRNAs have been reported to influence T helper differentiation. Here, we explored the underlying mechanism regarding how miRNAs regulate lymphocyte subsets in IgAN.

Methods

First, miRNA and mRNA profiles in PBMCs from IgAN patients and controls were obtained by next-generation sequencing and gene expression array. The target miRNAs and mRNAs were identified through combined analysis. Then, in an independent population, we detected the expression of target miRNA in CD3⁺ T cells and CD19⁺ B cells. Next, we detected T helper cell subgroups and plasma IgA1 levels in another independent population and analyzed the correlations between them.

Results

In total, 22 differentially expressed miRNAs were identified between IgAN patients and controls. Among them, microRNA-21-5p (miR-21) showed the highest expression, and SPRY1, SPRY2, and FASLG were chosen as miR-21 target genes. Then, we confirmed elevated miR-21 levels in CD3⁺ T cells of IgAN patients. Accordingly, decreased mRNA levels of SPRY1, SPRY2, and FASLG were found, and miR-21 showed a significant negative correlation with SPRY1 levels in CD3⁺ T cells of IgAN patients. Finally, we revealed that the proportion of Th17 cells was significantly elevated in IgAN patients and negatively correlated with SPRY1 expression. Furthermore, the proportion of Th17 cells showed a positive correlation trend with plasma IgA1 levels.

Conclusions

Our results suggested that in IgAN, the upregulated miR-21 expression in T lymphocytes inhibited SPRY1 expression and thereby induced Th17 polarization, which might influence the characteristic feature of IgA1 overproduction in IgAN patients.

McGrogan A, Franssen CF, de Vries CS (2011) The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transplant 26(2):414–430. https://doi.org/10.1093/ndt/gfq665 CrossRefPubMed

Le W, Liang S, Hu Y, Deng K, Bao H, Zeng C, Liu Z (2011) Long-term renal survival and related risk factors in patients with IgA nephropathy: results from a cohort of 1155 cases in a Chinese adult population. Nephrol Dial Transplant 27(4):1479–1485. https://doi.org/10.1093/ndt/gfr527 CrossRefPubMed

Suzuki H, Fan R, Zhang Z, Brown R, Hall S, Julian BA, Chatham WW, Suzuki Y, Wyatt RJ, Moldoveanu Z, Lee JY, Robinson J, Tomana M, Tomino Y, Mestecky J, Novak J (2009) Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J Clin Invest 119(6):1668–1677. https://doi.org/10.1172/jci38468 CrossRefPubMedPubMedCentral

Sun Y, Liu Z, Liu Y, Li X (2015) Increased frequencies of memory and activated B cells and follicular helper T cells are positively associated with high levels of activationinduced cytidine deaminase in patients with immunoglobulin A nephropathy. Mol Med Rep 12(4):5531–5537. https://doi.org/10.3892/mmr.2015.4071 CrossRefPubMed

Stuchlova Horynova M, Vrablikova A, Stewart TJ, Takahashi K, Czernekova L, Yamada K, Suzuki H, Julian BA, Renfrow MB, Novak J, Raska M (2015) N-acetylgalactosaminide alpha2,6-sialyltransferase II is a candidate enzyme for sialylation of galactose-deficient IgA1, the key autoantigen in IgA nephropathy. Nephrol Dial Transplant 30(2):234–238. https://doi.org/10.1093/ndt/gfu308 CrossRefPubMed

Zhai YL, Zhu L, Shi SF, Liu LJ, Lv JC, Zhang H (2016) Increased APRIL expression induces IgA1 aberrant glycosylation in IgA nephropathy. Medicine (Baltimore) 95(11):e3099. https://doi.org/10.1097/md.0000000000003099 CrossRef

Lai KN, Leung JC, Lai FM (1988) In vitro study of expression of interleukin-2 receptors in T-lymphocytes from patients with IgA nephropathy. Clin Nephrol 30(6):330–334PubMed

Ebihara I, Hirayama K, Yamamoto S, Muro K, Yamagata K, Koyama A (2001) Th2 predominance at the single-cell level in patients with IgA nephropathy. Nephrol Dial Transplant 16(9):1783–1789. https://doi.org/10.1093/ndt/16.9.1783 CrossRefPubMed

Suzuki H, Suzuki Y, Aizawa M, Yamanaka T, Kihara M, Pang H, Horikoshi S, Tomino Y (2007) Th1 polarization in murine IgA nephropathy directed by bone marrow-derived cells. Kidney Int 72(3):319–327. https://doi.org/10.1038/sj.ki.5002300 CrossRefPubMed

10.

Yang L, Zhang X, Peng W, Wei M, Qin W (2017) MicroRNA-155-induced T lymphocyte subgroup drifting in IgA nephropathy. Int Urol Nephrol 49(2):353–361. https://doi.org/10.1007/s11255-016-1444-3 CrossRefPubMed

11.

Carissimi C, Carucci N, Colombo T, Piconese S, Azzalin G, Cipolletta E, Citarella F, Barnaba V, Macino G, Fulci V (2014) miR-21 is a negative modulator of T-cell activation. Biochimie 107(Pt B):319–326. https://doi.org/10.1016/j.biochi.2014.09.021 CrossRefPubMed

12.

Li QJ, Chau J, Ebert PJ, Sylvester G, Min H, Liu G, Braich R, Manoharan M, Soutschek J, Skare P, Klein LO, Davis MM, Chen CZ (2007) miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129(1):147–161. https://doi.org/10.1016/j.cell.2007.03.008 CrossRefPubMed

13.

Lu TX, Hartner J, Lim EJ, Fabry V, Mingler MK, Cole ET, Orkin SH, Aronow BJ, Rothenberg ME (2011) MicroRNA-21 limits in vivo immune response-mediated activation of the IL-12/IFN-gamma pathway, Th1 polarization, and the severity of delayed-type hypersensitivity. J Immunol 187(6):3362–3373. https://doi.org/10.4049/jimmunol.1101235 CrossRefPubMedPubMedCentral

14.

Wang S, Wang J, Zhang Z, Miao H (2017) Decreased miR-128 and increased miR-21 synergistically cause podocyte injury in sepsis. J Nephrol 30(4):543–550. https://doi.org/10.1007/s40620-017-0405-y CrossRefPubMed

15.

Serino G, Sallustio F, Cox SN, Pesce F, Schena FP (2012) Abnormal miR-148b expression promotes aberrant glycosylation of IgA1 in IgA nephropathy. J Am Soc Nephrol 23(5):814–824. https://doi.org/10.1681/asn.2011060567 CrossRefPubMedPubMedCentral

16.

Serino G, Sallustio F, Curci C, Cox SN, Pesce F, De Palma G, Schena FP (2015) Role of let-7b in the regulation of N-acetylgalactosaminyltransferase 2 in IgA nephropathy. Nephrol Dial Transplant 30(7):1132–1139. https://doi.org/10.1093/ndt/gfv032 CrossRefPubMed

17.

Hu S, Bao H, Xu X, Zhou X, Qin W, Zeng C, Liu Z (2015) Increased miR-374b promotes cell proliferation and the production of aberrant glycosylated IgA1 in B cells of IgA nephropathy. FEBS Lett 589(24 Pt B):4019–4025. https://doi.org/10.1016/j.febslet.2015.10.033 CrossRefPubMed

18.

Zhao N, Hou P, Lv J, Moldoveanu Z, Li Y, Kiryluk K, Gharavi AG, Novak J, Zhang H (2012) The level of galactose-deficient IgA1 in the sera of patients with IgA nephropathy is associated with disease progression. Kidney Int 82(7):790–796. https://doi.org/10.1038/ki.2012.197 CrossRefPubMedPubMedCentral

19.

Peng Z, Tian J, Cui X, Xian W, Sun H, Li E, Geng L, Zhang L, Zhao P (2013) Increased number of Th22 cells and correlation with Th17 cells in peripheral blood of patients with IgA nephropathy. Hum Immunol 74(12):1586–1591. https://doi.org/10.1016/j.humimm.2013.08.001 CrossRefPubMed

20.

Li S, Fan Q, He S, Tang T, Liao Y, Xie J (2015) MicroRNA-21 negatively regulates Treg cells through a TGF-beta1/Smad-independent pathway in patients with coronary heart disease. Cell Physiol Biochem 37(3):866–878. https://doi.org/10.1159/000430214 CrossRefPubMed

21.

Murugaiyan G, da Cunha AP, Ajay AK, Joller N, Garo LP, Kumaradevan S, Yosef N, Vaidya VS, Weiner HL (2015) MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis. J Clin Invest 125(3):1069–1080. https://doi.org/10.1172/jci74347 CrossRefPubMedPubMedCentral

22.

Wang H, Fan H, Tao J, Shao Q, Ding Q (2019) MicroRNA-21 silencing prolongs islet allograft survival by inhibiting Th17 cells. Int Immunopharmacol 66:274–281. https://doi.org/10.1016/j.intimp.2018.11.022 CrossRefPubMed

23.

Chai C, Song LJ, Han SY, Li XQ, Li M (2018) MicroRNA-21 promotes glioma cell proliferation and inhibits senescence and apoptosis by targeting SPRY1 via the PTEN/PI3K/AKT signaling pathway. CNS Neurosci Ther 24(5):369–380. https://doi.org/10.1111/cns.12785 CrossRefPubMedPubMedCentral

24.

Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, Castoldi M, Soutschek J, Koteliansky V, Rosenwald A, Basson MA, Licht JD, Pena JT, Rouhanifard SH, Muckenthaler MU, Tuschl T, Martin GR, Bauersachs J, Engelhardt S (2008) MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456(7224):980–984. https://doi.org/10.1038/nature07511 CrossRefPubMed

25.

Choi H, Cho SY, Schwartz RH, Choi K (2006) Dual effects of Sprouty1 on TCR signaling depending on the differentiation state of the T cell. J Immunol 176(10):6034–6045. https://doi.org/10.4049/jimmunol.176.10.6034 CrossRefPubMed

26.

Milillo A, Molinario C, Costanzi S, Vischini G, La Carpia F, La Greca F, Rigante D, Gambaro G, Gurrieri F, Sangiorgi E (2018) Defective activation of the MAPK/ERK pathway, leading to PARP1 and DNMT1 dysregulation, is a common defect in IgA nephropathy and Henoch-Schonlein purpura. J Nephrol 31(5):731–741. https://doi.org/10.1007/s40620-018-0482-6 CrossRefPubMed

27.

Lee JS, Lee JE, Oh YM, Park JB, Choi H, Choi CY, Kim IH, Lee SH, Choi K (2009) Recruitment of Sprouty1 to immune synapse regulates T cell receptor signaling. J Immunol 183(11):7178–7186. https://doi.org/10.4049/jimmunol.0803799 CrossRefPubMed

28.

Christensen D, Mortensen R, Rosenkrands I, Dietrich J, Andersen P (2017) Vaccine-induced Th17 cells are established as resident memory cells in the lung and promote local IgA responses. Mucosal Immunol 10(1):260–270. https://doi.org/10.1038/mi.2016.28 CrossRefPubMed

29.

Elicabe RJ, Silva JE, Dave MN, Lacoste MG, Tamashiro H, Blas R, Munarriz A, Rabinovich GA, Di Genaro MS (2017) Association between IL-17 and IgA in the joints of patients with inflammatory arthropathies. BMC Immunol 18(1):8. https://doi.org/10.1186/s12865-017-0189-9 CrossRefPubMedPubMedCentral

30.

Cao AT, Yao S, Gong B, Elson CO, Cong Y (2012) Th17 cells upregulate polymeric Ig receptor and intestinal IgA and contribute to intestinal homeostasis. J Immunol 189(9):4666–4673. https://doi.org/10.4049/jimmunol.1200955 CrossRefPubMedPubMedCentral

31.

Fellstrom BC, Barratt J, Cook H, Coppo R, Feehally J, de Fijter JW, Floege J, Hetzel G, Jardine AG, Locatelli F, Maes BD, Mercer A, Ortiz F, Praga M, Sorensen SS, Tesar V, Del Vecchio L (2017) Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Lancet 389(10084):2117–2127. https://doi.org/10.1016/s0140-6736(17)30550-0 CrossRefPubMed

32.

Kiryluk K, Li Y, Scolari F, Sanna-Cherchi S, Choi M, Verbitsky M, Fasel D et al (2014) Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nat Genet 46(11):1187–1196. https://doi.org/10.1038/ng.3118 CrossRefPubMedPubMedCentral

Title: MicroRNA-21-5p participates in IgA nephropathy by driving T helper cell polarization
Authors: Bo-yang Xu
Si-jun Meng
Su-fang Shi
Li-jun Liu
Ji-cheng Lv
Li Zhu
Hong Zhang
Publication date: 01-06-2020
Publisher: Springer International Publishing
Published in: Journal of Nephrology / Issue 3/2020
Print ISSN: 1121-8428
Electronic ISSN: 1724-6059
DOI: https://doi.org/10.1007/s40620-019-00682-3

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2020

Systematic DOACs oral anticoagulation in patients with atrial fibrillation and chronic kidney disease: the nephrologist’s perspective

The renal adverse effects of cancer immunotherapy

COVID-19 and dialysis: why we should be worried

Management of dyslipidaemia in patients with chronic kidney disease: a position paper endorsed by the Italian Society of Nephrology

Recent insights into sodium and potassium handling by the aldosterone-sensitive distal nephron: implications on pathophysiology and drug discovery

Correction to: Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the UBI Study

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials