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Molecular and Immunological Basis of Tubulo-Interstitial Injury in Lupus Nephritis: a Comprehensive Review

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Abstract

Lupus nephritis is an important cause of kidney failure in patients of Asian, African, or Hispanic descent. Its etiology and pathogenesis are multifactorial and remain to be elucidated. Accumulating evidence suggests that anti-double-stranded DNA (dsDNA) antibodies play a critical role in the pathogenesis, through its direct binding to cross-reactive antigens on resident renal cells or indirect binding through chromatin material to extracellular matrix components, resulting in complement activation, cell activation and proliferation, and induction of inflammatory and fibrotic processes. While tubulo-interstitial damage portends poor long-term renal prognosis, the mechanisms leading to tubulo-interstitial injury in lupus nephritis has received relatively less attention to date. Immune deposition along the tubular basement membrane is often observed in lupus nephritis and correlates with tubulo-interstitial infiltration of immune cells and interstitial fibrosis. Anti-dsDNA antibodies bind to resident renal cells, including proximal renal tubular epithelial cells, and contribute to renal inflammation and fibrosis. There is emerging evidence that epigenetic influence such as DNA methylation, histone modification, and microRNAs (miRs) also contribute to kidney fibrosis. Overexpression of miR-150 is observed in renal biopsies from patients with lupus nephritis and correlates with kidney fibrosis and chronicity score. Mycophenolate mofetil (MMF) is an established and effective standard-of-care therapy for patients with lupus nephritis. Accumulating data suggest that in addition to its immunosuppressive actions on lymphocyte proliferation, mycophenolic acid (MPA), the active metabolite of MMF, can exert a direct effect on nonimmune cells. Mediators of inflammation and fibrosis induced by anti-dsDNA antibodies in cultured proximal renal tubular epithelial cells are ameliorated by the addition of MPA, suggesting that in addition to its immunosuppressive actions, MPA may also have a beneficial effect in improving tubulo-interstitial inflammation and fibrosis through its direct action on proximal renal tubular epithelial cells.

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Abbreviations

APOL1:

Apolipoprotein 1

CDR:

Complementarity-determining region

CpG:

Cytosine-phosphate-guanine

DNMT1:

DNA methyltransferase 1

dsDNA:

Double-stranded deoxyribonucleic acid

EMT:

Epithelial-to-mesenchymal transition

ERK:

Extracellular signal-regulated kinase

GBM:

Glomerular basement membrane

HAS2:

Hyaluronan synthase 2

HDAC:

Histone deacetylase

HLA:

Human leukocyte antigen

IgG:

Immunoglobulin G

IgM:

Immunoglobulin M

IL-6:

Interleukin-6

IL-8:

Interleukin-8

IMPDH:

Inosine monophosphate dehydrogenase

ITGAM:

Integrin alpha M

JNK:

C-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

MCP-1:

Monocyte chemoattractant protein-1

MHC:

Major histocompatibility complex

miR:

MicroRNA

MMF:

Mycophenolate mofetil

MPA:

Mycophenolic acid

NFκB:

Nuclear factor kappa B

NZB/W:

New Zealand black and white

PDGFRA:

Platelet-derived growth factor receptor alpha

PKC:

Protein kinase C

PTEC:

Proximal renal tubular epithelial cells

RASAL1:

Ras-GTPase-activating-like protein 1

RNA:

Ribonucleic acid

SCID:

Severe combined immunodeficiency

SLE:

Systemic lupus erythematosus

snRNP protein:

Small nuclear ribonuclear protein

SOCS1:

Suppressor of cytokine signaling 1

ss:

Single-stranded

STAT4:

Signal transducer and activator of transcription 4

TGF-β1:

Transforming growth factor beta1

TNF-α:

Tumor necrosis factor-alpha

TNFSF4:

Tumor necrosis factor superfamily member 4

TRL:

Toll-like receptor

UUO:

Unilateral urethral obstruction

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Acknowledgments

This study was funded by the RGC General Research Fund (HKU 7604/10M, HKU 7607/12M, and 17126814) and Merit Award, the University of Hong Kong Small Project Funding (201007176285), UGC Matching Grant Schemes (Phases IV, V, and VI), the Estate of the late Mr. Chan Wing Hei, and kind donations from Mr. G. King and Mr. C.S. Yung. S. Yung is supported by the Wai Hung Charitable Foundation Limited and the “Yu Chiu Kwong Chair in Medicine” Endowment Fund awarded to T.M. Chan.

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  1. Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pok Fu Lam, Hong Kong

    Susan Yung & Tak Mao Chan

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Yung, S., Chan, T.M. Molecular and Immunological Basis of Tubulo-Interstitial Injury in Lupus Nephritis: a Comprehensive Review. Clinic Rev Allerg Immunol 52, 149–163 (2017). https://doi.org/10.1007/s12016-016-8533-z

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