Complement 3 is involved in changing the phenotype of human glomerular mesangial cells

Wan, Jianxin; Fukuda, Noboru; Endo, Morito; Tahira, Yoshiko; Yao, En-Hui; Matsuda, Hiroyuki; Ueno, Takayoshi; Matsumoto, Koichí

doi:10.1002/jcp.21129

Cited by 44 publications

(24 citation statements)

References 34 publications

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“…These differences may relate to the ability of the heavy chain to activate complement, a property that light chains lack. Complement activation, which is typically detectable by immunofluorescence in these cases, may have direct effects on mesangial cells and podocytes to promote matrix production and greater proteinuria (19,20). Patient outcome, however, was not statistically different between HCDD and LCDD.…”

Section: Discussionmentioning

confidence: 89%

Renal Monoclonal Immunoglobulin Deposition Disease

Nasr¹,

Valeri²,

Cornell³

et al. 2012

Clinical Journal of the American Society of Nephrology

252

214

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SummaryBackground and objectives To better define the clinical-pathologic spectrum and prognosis of monoclonal immunoglobulin deposition disease (MIDD), this study reports the largest series.Design, setting, participants, & measurements Characteristics of 64 MIDD patients who were seen at Mayo Clinic are provided.Results Of 64 patients with MIDD, 51 had light chain deposition disease, 7 had heavy chain deposition disease, and 6 had light and heavy chain deposition disease. The mean age at diagnosis was 56 years, and 23 patients (36%) were #50 years of age. Clinical evidence of dysproteinemia was present in 62 patients (97%), including multiple myeloma in 38 (59%). M-spike was detected on serum protein electrophoresis in 47 (73%). Serum free light chain ratio was abnormal in all 51 patients tested. Presentation included renal insufficiency, proteinuria, hematuria, and hypertension. Nodular mesangial sclerosis was seen in 39 patients (61%). During a median of 25 months of follow-up (range, 1-140) in 56 patients, 32 (57%) had stable/improved renal function, 2 (4%) had worsening renal function, and 22 (39%) progressed to ESRD. The mean renal and patient survivals were 64 and 90 months, respectively. The disease recurred in three of four patients who received a kidney transplant.Conclusions Patients with MIDD generally present at a younger age than those with light chain amyloidosis or light chain cast nephropathy. Serum free light chain ratio is abnormal in all MIDD patients, whereas only threequarters have abnormal serum protein electrophoresis. The prognosis for MIDD is improving compared with historical controls, likely reflecting earlier detection and improved therapies.

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Section: Discussionmentioning

confidence: 89%

Renal Monoclonal Immunoglobulin Deposition Disease

Nasr¹,

Valeri²,

Cornell³

et al. 2012

Clinical Journal of the American Society of Nephrology

252

214

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“…The capacity of C3a to induce a change in the phenotype of other renal cells has also been reported. Wan et al 45 demonstrated that C3a can change the phenotype of mesangial cells, which may have implications for understanding the effect of C3a in this mouse model of proteinuria.…”

Section: Discussionmentioning

confidence: 94%

C3a Mediates Epithelial-to-Mesenchymal Transition in Proteinuric Nephropathy

Tang¹,

Lu²,

Hatch³

et al. 2009

Journal of the American Society of Nephrology

122

115

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Tubulointerstitial inflammation and progressive fibrosis are common pathways that lead to kidney failure in proteinuric nephropathies. Activation of the complement system has been implicated in the development of tubulointerstitial injury in clinical and animal studies, but the mechanism by which complement induces kidney injury is not fully understood. Here, we studied the effect of complement on the phenotype of tubular epithelial cells. Tubular epithelial cells exposed to serum proteins adopted phenotypic and functional characteristics of mesenchymal cells. Expression of E-cadherin protein decreased and expression of both ␣-smooth muscle actin protein and collagen I mRNA increased. Exposure of the cells to the complement anaphylotoxin C3a induced similar features. Treating with a C3a receptor (C3aR) antagonist prevented both C3a-and serum-induced epithelial-to-mesenchymal transition. In the adriamycin-induced proteinuria model, C3aR-deficient mice demonstrated less injury, preserved renal function, and improved survival compared with wild-type mice. Furthermore, the kidneys of C3aR-deficient mice had significantly less interstitial collagen I and ␣-smooth muscle actin. In summary, the complement anaphylotoxin C3a is an important mediator of glomerular and tubulointerstitial injury and can induce tubular epithelial-to-mesenchymal transition.

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“…Mesangial cells produce FH 86 and, in an inflammatory environment (IL-1 or TNFa), they produce C3. 87 Furthermore, the autoantigen in IgAN, polymeric Gd-IgA1, can itself stimulate mesangial cells to produce and secrete C3. 88 Activation products C3a and C5a can induce cultured human mesangial cells to produce DAF, a potent membrane-bound regulator of the alternative pathway.…”

Section: Where Complement Is Activated: From Soluble Circulating Immumentioning

confidence: 99%

“…This transition may explain the in vivo expansion of the mesangial matrix commonly observed in renal biopsies of patients with IgAN. 87 The effect has been shown to be dependent on C3a receptor, although another study using in situ hybridization failed to find C3a receptor expression on normal human mesangial cells. 91 …”

Section: Where Complement Is Activated: From Soluble Circulating Immumentioning

confidence: 99%