LPS-evoked IL-18 expression in mesangial cells plays a role in accelerating lupus nephritis

Shui, Hao‐Ai; Ka, Shuk‐Man; Wu, Wen-Yih; Lin, Yun-Lian; Hou, Yan-qiang; Su, Le; Chen, A.

doi:10.1093/rheumatology/kem136

Cited by 39 publications

(56 citation statements)

References 34 publications

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“…10 Although this model is similar to the anti-Thy1 nephritis model in rats, the degree of mesangiolysis is not as profound (data not shown; see Yo et al 10 ) and requires additional application of LPS to aggravate mesangial injury. 11,12 In several pilot experiments combining anti-mesangial cell serum with varying doses of either Habu snake venom (data not shown) or LPS, we determined the best model system with maximal mesangial cell injury without an increase in mortality, which was used for all further experiments. On days 2-3, the optimized LPS/anti-mesangial cell serum-induced experimental disease model revealed overall pronounced mesangiolysis at varying degrees in individual glomeruli, which was followed by cellular repopulation up to days 10-13 ( Figure 1) as indicated by several lines of evidence.…”

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Renin Lineage Cells Repopulate the Glomerular Mesangium after Injury

Starke

Betz

Hickmann

et al. 2015

Journal of the American Society of Nephrology

100

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Mesangial cell injury has a major role in many CKDs. Because renin-positive precursor cells give rise to mesangial cells during nephrogenesis, this study tested the hypothesis that the same phenomenon contributes to glomerular regeneration after murine experimental mesangial injury. Mesangiolysis was induced by administration of an anti-mesangial cell serum in combination with LPS. In enhanced green fluorescent protein-reporter mice with constitutively labeled renin lineage cells, the size of the enhanced green fluorescent protein-positive area in the glomerular tufts increased after mesangial injury. Furthermore, we generated a novel Tet-on inducible triple-transgenic LacZ reporter line that allowed selective labeling of renin cells along renal afferent arterioles of adult mice. Although no intraglomerular LacZ expression was detected in healthy mice, about two-thirds of the glomerular tufts became LacZ positive during the regenerative phase after severe mesangial injury. Intraglomerular renin descendant LacZ-expressing cells colocalized with mesangial cell markers a8-integrin and PDGF receptor-b but not with endothelial, podocyte, or parietal epithelial cell markers. In contrast with LacZ-positive cells in the afferent arterioles, LacZ-positive cells in the glomerular tuft did not express renin. These data demonstrate that extraglomerular renin lineage cells represent a major source of repopulating cells for reconstitution of the intraglomerular mesangium after injury.

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confidence: 99%

Renin Lineage Cells Repopulate the Glomerular Mesangium after Injury

Starke

Betz

Hickmann

et al. 2015

Journal of the American Society of Nephrology

100

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“…[25][26][27][28][29][30] Macrophage accumulation in association with increased IL-18 expression has been described in a number of inflammatory and immune-mediated processes. 29,31 We previously described IL-18 upregulation within the kidney during acute rejection in a kidney allograft model and found intragraft macrophages to be the major source.…”

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confidence: 99%

IL-18 Contributes to Renal Damage after Ischemia-Reperfusion

Craft

Wang

et al. 2008

Journal of the American Society of Nephrology

179

118

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“…Their further in vitro studies suggested that up regulation of renal IL-18 is a prerequisite for the local inflammatory cytokine cascade especially that the interaction between TNF and IL-18 might provide a positive-amplification loop that accelerates the auto-immune kidney disease. In addition to a possible role of IL-18 in the induction of apoptosis in tubular epithelial cells, 13 Shui et al 40 also demonstrated IL-18 overexpression, associated with hyperplasia and apoptosis of mesangial cells in the glomeruli of lipopolysaccharid-accelerated LN mice. They suggested that local IL-18 in the nephritic kidneys could act like a paracrine cytokine to exacerbate glomerular inflammation and is probably involved in the apoptosis of the downstream tubular cells.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-18 as a Biomarker of Subclinical Lupus Nephritis

et al. 2015

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Objectives:This study aims to investigate the relationship between serum interleukin-18 (IL-18) and its renal expression with histological classification of lupus nephritis in patients with insignificant proteinuria, and evaluate serum IL-18 as a biomarker of subclinical renal involvement in lupus patients. Patients and methods: Forty lupus patients (5 males, 35 females; mean age 26.3±7.9 years; range 16 to 52 years) with proteinuria less than 0.5 g/24 hours and 20 healthy controls (2 males, 18 females, mean age 25.5±6.3 years; range 16 to 49 years) were included. Patients underwent full history taking, thorough clinical examination, assessment of disease activity, measurement of serum IL-18, and renal biopsies for histopathological assessment and immunostaining for tissue expression of IL-18. Results: Lupus patients had significantly higher serum IL-18 levels than controls (612.4 and 209.3 pg/mL, respectively; p<0.01). Serum IL-18 was significantly higher in patients with classes III, IV and V lupus nephritis (609.1, 833.1 and 790 pg/mL, respectively) than in patients with class I and II (370 and 476.8 pg/mL, respectively). Immunostaining of IL-18 showed glomerular expression in classes IV and V, glomerular and tubular infiltration in class III, tubular pattern in class II and no staining in class I. Patients with diffuse glomerular IL-18 staining had higher levels of serum IL-18 than those with no staining (840.8 and 522.9 pg/mL, respectively; p=0.0). Those with diffuse tubular IL-18 staining had higher levels of serum IL-18 than those with no staining (514.2 and 393 pg/mL, respectively; p<0.05). Serum IL-18 correlated with serum creatinine and the activity index of renal biopsies. Conclusion: IL-18 may play a role in the pathogenesis of lupus nephritis. Results of this study showed that serum IL-18 reflects the extent of renal injury in lupus even in absence of significant proteinuria regardless of the level of disease activity; proposing its early role in pathogenesis of lupus nephritis. Thus serum IL-18 can be used as a biomarker that distinguishes the different histological classes of subclinical lupus nephritis.

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LPS-evoked IL-18 expression in mesangial cells plays a role in accelerating lupus nephritis

Abstract: We conclude that LPS can evoke IL-18 production in MCs, but neither LPS nor IL-18 directly induces apoptosis or activates apoptotic signal transduction in the cells. We infer that LPS-induced IL-18 production by MCs could be a mediator by which LPS accelerates and exacerbates LN.

Cited by 39 publications

References 34 publications

Renin Lineage Cells Repopulate the Glomerular Mesangium after Injury

Renin Lineage Cells Repopulate the Glomerular Mesangium after Injury

IL-18 Contributes to Renal Damage after Ischemia-Reperfusion

Interleukin-18 as a Biomarker of Subclinical Lupus Nephritis

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