TGF-β1 Induces Aberrant Laminin Chain and Collagen Type IV Isotype Expression in the Glomerular Basement Membrane

Chai, Qing; Krag, Susanne; Miner, Jeffrey H.; Nyengaard, Jens Randel; Chai, Song; Wogensen, Lise

doi:10.1159/000072496

Cited by 23 publications

(29 citation statements)

References 44 publications

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“…Consistent with an elevation of ECM synthesis pathways, we also observed increased expression of the collagen genes Col1A1, Col1A2, Col3A1, Col4A1 and Col4A2. It is of particular interest to note that increased TGF-β signaling in vivo has previously been shown to induce aberrant collagen type IV isotype (4A1 and 4A2) synthesis in the glomerular basement membrane of the kidney [26]. We also observed increased expression of the versican gene in nephrotic samples.…”

Section: Resultssupporting

confidence: 57%

Microarray Analysis of Focal Segmental Glomerulosclerosis

Schwab¹,

Witte²,

Aronow³

et al. 2004

Am J Nephrol

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Background: Focal segmental glomerulosclerosis (FSGS) is a leading cause of chronic renal failure in children. Recent studies have begun to define the molecular pathogenesis of this heterogeneous condition. Here we use oligonucleotide microarrays to obtain a global gene expression profile of kidney biopsy specimens from patients with FSGS in order to better understand the pathogenesis of this disease. Methods: We extracted RNA from renal biopsy samples of 10 patients with the diagnosis of FSGS and from 5 control kidney samples, and produced labeled cRNA for hybridization to Affymetrix human U133A microarrays. Results: We identified a gene expression fingerprint for FSGS that contained 429 of 22,283 possible genes, each with a p < 0.01, using RMA normalization, Welch t test, and at least a 1.8-fold change in 5 of the 10 patients examined. We also found gene expression differences in samples from subsets of patients who had either nephrotic syndrome or renal insufficiency. This screen identified many genes and genetic pathways that have already been implicated in the pathogenesis of FSGS. In addition, we found changes in gene expression in genetic pathways that have not been studied in FSGS. Conclusions: Oligonucleotide DNA microarray analysis of renal biopsy specimens identified a gene expression fingerprint in samples from a heterogeneous population of patients with FSGS. The genes and genetic pathways identified in this study can be compared to results of similar studies of other diseases to examine specificity and used to study the pathogenesis of FSGS.

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Section: Resultssupporting

confidence: 57%

Microarray Analysis of Focal Segmental Glomerulosclerosis

Schwab¹,

Witte²,

Aronow³

et al. 2004

Am J Nephrol

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“…Interestingly, during infection and inflammation, TGF␤1 has specifically been shown to induce an aberrant laminin ␤1 chain expression in the kidney (12). We also found that nucleosomes associated only with laminins containing the ␤1 chain in the GBM and in the mesangial matrix of patients with lupus nephritis, which led us to hypothesize that local TGF␤1 may play an important role in the pathogenesis of lupus nephritis.…”

mentioning

confidence: 65%

“…This feature has also been demonstrated experimentally using TGF␤1-transgenic animals (12,22). Bioactive TGF may derive from the circulation, the juxtaglomerular apparatus, or the glomerular cells themselves during infections and inflammation (30,31).…”

Section: Discussionmentioning

confidence: 86%

“…We investigated differences in nucleosome binding to the individual laminin ␤1 and ␤2 chains, since ␤1 represents an immature form of laminin, which we found to be expressed in vivo during lupus nephritis (see below) and which has been reported to be seen during inflammatory conditions, such as viral infections (12). The laminins investigated above that were found to bind nucleosomes all have the laminin ␤1 chain in common.…”

Section: Resultsmentioning

confidence: 99%

“…In the latter cases, the latent pool of TGF␤ constitutively secreted as inactive forms is attenuated by the production of a postulated "inducer" from the glomerular cells (32,33). TGF␤1 induces the expression, and thus the deposition, of type IV collagen as well as aberrant fetal laminin ␣1, ␣2, and ␤1 chains, into the GBM (12). Simultaneously, TGF␤1 blocks matrix degradation by decreasing the synthesis of proteases and by increasing the levels of protease inhibitors (34).…”

Section: Discussionmentioning

confidence: 99%

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Pathogenic Mechanisms in Lupus Nephritis: Nucleosomes Bind Aberrant Laminin β1 With High Affinity and Colocalize in the Electron‐Dense Deposits

Olin

Mörgelin

Truedsson

et al. 2014

Arthritis & Rheumatology

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Objective. Apoptotic nucleosomes are structurally and immunologically involved in lupus nephritis. The purpose of this study was to examine the expression and function of laminins and their interactions with nucleosomes in the kidneys of patients with lupus nephritis, using surface plasmon resonance (SPR) analysis.Methods. SPR interaction analysis was used to quantify the strength of laminin-nucleosome interactions. Electron microscopy techniques were used to determine in vivo colocalization of IgG, chromatin, and laminin ␤1, as well as to characterize nucleosomelaminin interactions in vitro.Results. Nucleosomes were found to possess high affinity for laminin ␤1-containing laminins and to have the potential to form stable molecular complexes with these structures. In vivo, laminin ␤1 was aberrantly expressed in the glomerular basement membrane (GMB) of lupus nephritis patients, and in situ, it acted as a nucleosome ligand, selectively colocalizing with nucleosomes within electron-dense deposits (EDDs). Normal adult laminin 11, which contains laminin ␤2, did not bind nucleosomes, and it did not colocalize in vivo with the nucleosomes in the nephritic GBM. In addition, TGF␤1 was expressed by the glomerular mesangium, glomerular endothelial cells, and by podocytes in patients with lupus nephritis. It was trapped in situ within EDDs by an as-yet-unknown ligand. As was recently described in a transgenic mouse model, paracrine kidney glomerular TGF␤1 may thereby contribute to the development of glomerulopathy via the induction of laminin ␤1 incorporation in the GBM, whereas systemic blood vessel-derived TGF␤1 could be trapped during filtration.Conclusion. Our findings of the specific highaffinity binding of nucleosomes to aberrantly expressed laminin ␤1 in the GBM and their colocalization in the GBM may explain important features of the initial steps in the pathogenesis of lupus nephritis, the planted antigen hypothesis.

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Effects of tripterine on mRNA expression of TGF‐β1 and collagen IV expression in BW F1 mice

Zhong

et al. 2006

Cell Biochemistry & Function

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Tripterine is a chemical isolated from a traditional Chinese herb which had been testified for its anti-inflammatory and immunosuppressive activities in a previous study. However, little is known about the effects and mechanism of action of Tripterine on treating lupus nephritis. In the present study we investigated the effect of Tripterine on the F1 hybrids of New Zealand Black (NZB) and New Zealand White (NZW) mice which functioned as a model of human systemic lupus erythematosus (BW F1 mice) and evaluated the possible mechanism implicated in the mRNA expression of TGF-beta1 and collagen IV expression of the BW F1 mice kidney tissue. Different doses of Tripterine were injected peritoneally to BW F1 mice at different stages to study the preventive effects of Tripterine on lupus nephritis glomerulosclerosis and its mechanisms. Twenty-four hour urine protein excretion, serum anti-dsDNA antibodies and the expression of collagen type IV were examined by immunohistochemistry while the expression of TGF-beta1 mRNA was detected by RT nested PCR. Tripterine decreased urine protein excretion and the level of serum anti-dsDNA antibodies and also suppressed the expression of collagen type IV and TGF-beta1 mRNA in the murine kidney tissue. Administration of Tripterine before the occurrence of proteinuria had much greater protective effects than if it was administered after the occurrence of proteinuria. No significant difference was found between the 3 mg/kg/week Tripterine-treated-group and the 6 mg/kg/week Tripterine-treated-group. Tripterine had a definite protective effect on glomerulosclerosis of the lupus murine model. Tripterine could significantly reduce the amount of urine protein excretion, suppress the formation of serum anti-dsDNA antibodies, it could also efficiently decrease the expression of renal collagen type IV probably due to its suppressive effect on the expressions of local TGF-(1 mRNA) in this model.

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TGF-β1 Induces Aberrant Laminin Chain and Collagen Type IV Isotype Expression in the Glomerular Basement Membrane

Cited by 23 publications

References 44 publications

Microarray Analysis of Focal Segmental Glomerulosclerosis

Microarray Analysis of Focal Segmental Glomerulosclerosis

Pathogenic Mechanisms in Lupus Nephritis: Nucleosomes Bind Aberrant Laminin β1 With High Affinity and Colocalize in the Electron‐Dense Deposits

Effects of tripterine on mRNA expression of TGF‐β1 and collagen IV expression in BW F1 mice

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