Lipopolysaccharide-Triggered Acute Aggravation of Mesangioproliferative Glomerulonephritis through Activation of Coagulation in a High IgA Strain of ddY Mice

Shimosawa, Makiko; Sakamoto, Koji; Tomari, Yuki; Kamikado, Kohei; Otsuka, Hidetaka; Liu, Ning; Kitamura, Hisayo; Uemura, Kazuhide; Nogaki, Fumiaki; Mori, Noriko; Muso, Eri; Yoshida, Haruyoshi; Ono, Takahiko

doi:10.1159/000224798

Cited by 11 publications

(5 citation statements)

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“…7 As the marker of gram negative bacterial infections, lipopolysaccharide (LPS) could trigger an acute aggravation of mesangioproliferative glomerulonephritis, induce experimental IgAN, and suppress C1GALT1C1 expression in patients with IgAN. [8][9][10] Therefore, this study was designed to determine whether LPS could induce aberrant IgA1 O-glycosylation by suppressing C1GALT1C1 expres-sion.…”

mentioning

confidence: 99%

The role of C1GALT1C1 in lipopolysaccharide-induced IgA1 aberrant O-glycosylation in IgA nephropathy

Xie

Qin²,

Fan³

et al. 2010

CIM

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Purpose: IgA1 aberrant O-glycosylation is one of the main pathogenetic features of IgA nephropathy (IgAN). This study attempted to determine the role of C1GALT1C1 in aberrant IgA1 O-glycosylation induced by lipopolysaccharide (LPS) and identify potential therapeutic targets in IgAN. Methods: Lymphocytes isolated from 22 patients with IgAN and 17 normal controls were cultured for 3 to 7 days with or without LPS and 5-azacytidine (5-AZA). Expression levels of C1GALT1C1 mRNA and protein were measured by real-time PCR and Western blot analysis, respectively. Concentration of IgA1 and level of O-glycosylation were determined by ELISA and Vicia villosa (VV) lectin-binding assay. Correlation analysis was performed between the expression of C1GALT1C1 protein and IgA1 O-glycosylation. Results: Lymphocytes from patients with IgAN secreted more IgA1 than that from normal controls after LPS stimulation (P=0.26, 0.002 and 0.005 on the 3rd, 5th and 7th day, respectively) which could be inhibited by 5-AZA (P=0.001, 0.025 and 0.001 on the 3rd, 5th and 7th day, respectively). Moreover, LPS stimulation could obviously inhibit C1GALT1C1 expression in patients with IgAN (decreased by 71%, 82% and 92% on the 3rd, 5th and 7th day, respectively; P < 0.001), and cause a significant decrease of IgA1 O-glycosylation compared with normal controls (P=0.004, 0.003 and 0.03 on the 3rd, 5th and 7th day, respectively). When 5-AZA was added, the level of C1GALT1C1 expression increased dramatically (1.98, 5.53 and 8.97 times on the 3rd, 5th and 7th day, respectively; P < 0.001) along with an increase of IgA1 O-glycosylation (P=0.295, 0.09 and 0.003 on the 3rd, 5th and 7th day, respectively). However, normal controls showed no significant change in C1GALT1C1 expression and IgA1 O-glycosylation after LPS stimulation (P > 0.05). Conclusion: LPS induced IgA1 aberrant O-glycosylation and suppressed C1GALT1C1 expression in patients with IgAN. Upregulation of C1GALT1C1 expression by 5-AZA could reverse the IgA1 aberrant O-glycosylation. These results suggest that C1GALT1C1 may play a key role in the regulation of IgA1 O-glycosylation.

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mentioning

confidence: 99%

The role of C1GALT1C1 in lipopolysaccharide-induced IgA1 aberrant O-glycosylation in IgA nephropathy

Xie

Qin²,

Fan³

et al. 2010

CIM

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“…Human serum IgA has both pro-inflammatory and anti-inflammatory properties in LPS-stimulated monocytes and peripheral blood mononuclear cells 18,19. Shimosawa, et al20 reported that mesangial TLR4 expression decreased after LPS administration in a high IgA strain of ddY mice, while mesangial proliferation, macrophage infiltration, and MCP-1 mRNA expression increased. The modified mesangial responses to LPS and IgA observed in our study might contribute to the feedback mechanisms maintaining a balance between pro-inflammatory and anti-inflammatory activities.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Signaling is Involved in IgA-Stimulated Mesangial Cell Activation

et al. 2011

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PurposeDeposition of polymeric IgA1 in the kidney mesangium is the hallmark of IgA nephropathy, but the molecular mechanisms of IgA-mediated mesangial responses and inflammatory injuries remain poorly understood. We hypothesize that Toll-like receptor 4 (TLR4) is involved in IgA-induced mesangial cell activation.Materials and MethodsMouse mesangial cells were stimulated with lipopolysaccharide (LPS) (1 µg/mL), IgA (20 µg/mL), or both, and TLR4 expression was measured by real time RT-PCR and Western blot. Intracellular responses to LPS or IgA were assessed by Western blot for ERK1/2, JNK, p38 MAP kinases (MAPKs), Iκ-Bα degradation and fibronectin secretion. MCP-1 secretion was assessed by ELISA. Small interfering RNA (siRNA) of TLR4 was used to confirm that the effects were caused by TLR4 activity.ResultsLPS- or IgA-treatment upregulated the levels of TLR4 mRNA and protein in cultured MMC at 24 h. LPS and IgA induced rapid phosphorylation of MAPKs, but degradation of Iκ-Bα was observed only in LPS-treated MMC. LPS, but not IgA, induced increased secretion of MCP-1 and fibronectin at 24 h or 48 h. Combined LPS and IgA treatment did not cause additional increases in TLR4 mRNA and protein levels or Iκ-Bα degradation, and MCP-1 and fibronectin secretions were less than with LPS alone. LPS- or IgA-induced TLR4 protein levels and MAPK activation were inhibited by transfection with TLR4 siRNA.ConclusionThese results indicate that the activation of MAPKs and MCP-1 secretion are mediated by TLR4, at least in part, in IgA-treated mesangial cells. TLR4 is involved in mesangial cell injury by induction of pro-inflammatory cytokines in IgA nephropathy.

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“…For example, vascular leakage is a hallmark of sepsis or noninfectious tissue injury, because PAMPs increase vascular permeability by activating TLRs on vascular endothelial cells. 60,61 The same mechanism enhances proteinuria during immune complex glomerulonephritis as shown for systemic LPS exposure from Gram-negative bacteria 11,62,63 or lipoprotein from Gram-positive bacteria. 63 These bacterial cell wall components enhance the permeability of glomerular endothelial cell and podocyte monolayers by activating surface TLR2 and TLR4.…”

Section: How Infections Can Trigger Flares Of Autoimmune Kidney Diseasementioning

confidence: 91%

Innate immune receptors and autophagy: implications for autoimmune kidney injury

Anders

Schlöndorff

2010

Kidney International

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Inflammation is the immune system's response to infectious or noninfectious sources of danger. Danger recognition is facilitated by various innate immune receptor families including the Toll-like receptors (TLRs), which detect danger signals in extracellular and intracellular compartments. It is an evolving concept that renal damage triggers intrarenal inflammation by immune recognition of molecules that are being released by dying cells. Such danger-associated molecules act as immunostimulatory agonists to TLRs and other innate immune receptors and induce cytokine and chemokine secretion, leukocyte recruitment, and tissue remodeling. As a new entry to this concept, autophagy allows stressed cells to reduce intracellular microorganisms, protein aggregates, and cellular organelles by moving and subsequently digesting them in autophagolysosomes. Within the autophagolysosome, endogenous molecules and danger-associated molecules may be presented to TLRs or loaded onto the major histocompatibility complex and presented as autoantigens. Here we discuss the current evidence for the danger signaling concept in autoimmune kidney injury and propose that autophagy-related processing of self-proteins provides a source of immunostimulatory molecules and autoantigens. A better understanding of danger signaling should enable us to unravel yet unknown triggers for renal immunopathology and progressive kidney disease.

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Lipopolysaccharide-Triggered Acute Aggravation of Mesangioproliferative Glomerulonephritis through Activation of Coagulation in a High IgA Strain of ddY Mice

Cited by 11 publications

References 94 publications

The role of C1GALT1C1 in lipopolysaccharide-induced IgA1 aberrant O-glycosylation in IgA nephropathy

The role of C1GALT1C1 in lipopolysaccharide-induced IgA1 aberrant O-glycosylation in IgA nephropathy

Toll-Like Receptor 4 Signaling is Involved in IgA-Stimulated Mesangial Cell Activation

Innate immune receptors and autophagy: implications for autoimmune kidney injury

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