Dietary Zinc Is a Key Environmental Modifier in the Progression of IgA Nephropathy

Masayuki Maiguma,Masahiro Muto,Keiko Okazaki,Hitoshi Suzuki,Yusuke Suzuki,Masashi Aizawa,Yasuhiko Tomino,Jörg Hermann Fritz

doi:10.1371/journal.pone.0090558

Abstract

IgA nephropathy (IgAN) shows diverse epidemiological characteristics, resulting from both genetic and acquired (e.g., environmental) causes. Environmental factors, such as diet or exposure to exogenous antigens, may prescribe the progression or prognosis of IgAN. It remains unclear as to how diet and infection influence susceptibility to IgAN. A relationship, such as Toll-like receptors (TLRs), especially TLR9 and TLR4, was demonstrated between IgAN and pathogen-recognition molecules. Recently, zinc (Zn) was discovered to be involved in various immune-related diseases, affecting B, T, and dendritic cells (DCs). This study investigates the relationship between dietary Zn and IgAN development in IgAN-prone mice. Seven-week-old IgAN-prone mice were divided into low, normal, and high Zn diet groups. To assess exogenous pathogen-mediated immune responses, lipopolysaccharide (LPS) was nasally administered. The activity of IgAN was biochemically and pathologically evaluated during the disease course. We also examined in vitro IgA production in spleen cells or in combinations of cocultured B, T, and DCs under various Zn conditions with or without LPS. Dietary conditioning with Zn affected serum immunoglobulins and urinary albumin levels, and mesangial deposition of IgA and IgG. Zn deficiency is associated with IgAN progression through the activation of the TLR4/TIR-domain-containing adapter-inducing interferon-β (TRIF), but not the TLR9, in DCs. Zn supplementation prevented disease aggravation. Our findings indicate that immune conditioning with dietary Zn alters nephritogenic IgA production after mucosal infection.

Highlights

First described by Berger et al in 1968 [1], IgA nephropathy (IgAN) is the most common primary chronic glomerulonephritis worldwide
The changes in the serum concentrations of IgA and IgA–IgG ICs after LPS stimulation was clearly suppressed in the high Zn diet group. These results suggest that dietary Zn levels influence the TLR4mediated progression of murine IgAN
To confirm the functional alteration of the TLR4/TIR-domain-containing adapter-inducing interferon-b (TRIF) pathway caused by Zn, we examined the expression of interferon-b, which is induced by the activation of the TRIF-dependent pathway following TLR4 activation [28,29]

Summary

Introduction

First described by Berger et al in 1968 [1], IgA nephropathy (IgAN) is the most common primary chronic glomerulonephritis worldwide. Johnson et al [7] suggested that environmental factors, such as exposure to antigens, affect the immune system and explain the difference in IgAN prevalence between developing and industrial countries. Nasal challenge with CpG DNA (a ligand of TLR9) exacerbated glomerular damage and was accompanied by increases in serum IgA concentration and mesangial IgA deposition in these mice. This suggested that mucosal stimulation of TLR may be linked, in part, to production of nephritogenic IgA. Coppo et al [10] reported a significant correlation between TLR4 expression on circulating mononuclear (CD14+) cells and the levels of proteinuria and the phases of clinical activity in patients with IgAN. TLR-mediated innate immunity may be significantly involved in IgAN progression

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Conclusion