Genomic analysis of a mouse model of immunoglobulin A nephropathy reveals an enhanced PDGF–EDG5 cascade

Katsuma, Susumu; Shiojima, Satoshi; Hirasawa, Akira; Suzuki, Yasuhito; Takagaki, Kazuchika; Murai, Masatoshi; Kaminishi, Yoshinori; Hada, Yuko; Koba, Masahiro; Muso, Eri; Miyawaki, Shigeki; Ohgi, Tadaaki; Yano, Junichi; Tsujimoto, Gozoh

doi:10.1038/sj.tpj.6500043

Cited by 18 publications

(14 citation statements)

References 42 publications

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“…Expression profiling was carried out by using mRNA from the renal cortex of anti-GBM GN or control rats on day 28 and cDNA microarrays enriched for clones representing rat kidney genes (16). We selected 43 of 3,000 cDNAs that were examined, in which the expression levels differed by Ͼ2-fold intensity from controls ( Table 2, which is published as supporting information on the PNAS web site).…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of protein kinase CK2 prevents the progression of glomerulonephritis

Yamada

Katsuma²,

Adachi³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Glomerulonephritis (GN) is a progressive inflammation that may be caused by a variety of underlying disorders. It is the primary cause of chronic renal failure and end-stage renal disease, which require dialysis and transplantation worldwide. Immunosuppressive therapy has been used to treat GN clinically, but this treatment has had insufficient therapeutic effects. Here, we show that protein kinase CK2 is a key molecule in the progression of GN. cDNA microarray analysis identified CK2␣, the catalytic subunit of CK2, as a GNrelated, differentially expressed gene. Overexpression of CK2␣ was noted in the proliferative glomerular lesions in rat GN models and in renal biopsy specimens from lupus nephritis or IgA nephropathy patients. Administration of either antisense oligodeoxynucleotide against CK2␣ or low molecular weight CK2-specific inhibitors effectively prevented the progression of renal pathology in the rat GN models. The resolution of GN by CK2 inhibition may result from its suppression of extracellular signal-regulated kinase-mediated cell proliferation, and its suppression of inflammatory and fibrotic processes that are enhanced in GN. Our results show that CK2 plays a critical role in the progression of immunogenic renal injury, and therefore, CK2 is a potential target for GN therapy.antisense oligodeoxynucleotide ͉ microarray ͉ pharmacology G lomerulonephritis (GN) is a disease characterized by renal inflammation, causing destruction of glomeruli and adjacent structures, as well as loss of renal function. It is associated with conditions such as hematuria and proteinuria. Current treatment is still limited to supportive therapy, with or without nonspecific immunosuppressive drugs (1-3). Early cellular proliferation followed by subsequent fibrosis is a prominent hallmark of proliferative GN, and it may ultimately lead to end-stage renal disease (4). The involvement of extracellular stimuli, such as growth factors, cytokines, activated complement, and immune complexes in the pathogenesis of experimental and human GN has been known for many years. However, only recently have the intracellular mediators that transduce signals from noxious extracellular stimuli to unfettered cellular proliferation and accompanying excess extracellular matrix deposition begun to be unraveled (5). Experiments with cultured glomerular cells and certain animal models of experimental GN implicate the activation of extracellular signal-regulated kinase (ERK), which results in glomerular cellular proliferation (6).Protein kinase CK2 (formerly known as casein kinase II) is an extremely well conserved pleiotropic protein kinase with a growing list of Ͼ300 substrates, the majority of which are proteins implicated in signal transduction, gene expression, and transcription-related functions (7-11). Protein kinase CK2 is a ubiquitous heterotetrameric serine͞threonine protein kinase made up of two ␣ or ␣Ј catalytic subunits and two ␤-regulatory subunits. CK2 is activated during cell division, cellular differentiation, and embryogenesis, an...

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Section: Resultsmentioning

confidence: 99%

“…cDNA microarray experiments were performed as described (16,17). We selected genes with average residuals that were more than ϩ1 or less than Ϫ1, i.e., that represented a 2-fold difference in expression level.…”

Section: As-odnmentioning

confidence: 99%

Inhibition of protein kinase CK2 prevents the progression of glomerulonephritis

Yamada

Katsuma²,

Adachi³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…It is well known that TGF‐β is a potent inducer of CTGF in mesangial cells and this induction is mediated through the Smad pathways [1,28]. These suggest that S1P and TGF‐β may cooperate in the enhanced CTGF expression via Smad pathways, leading to the progression of fibrotic renal disorders, such as IgAN [30].…”

Section: Resultsmentioning

confidence: 99%

Transcriptional regulation of connective tissue growth factor by sphingosine 1‐phosphate in rat cultured mesangial cells

et al. 2005

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Connective tissue growth factor (CTGF) is induced by transforming growth factor-b (TGF-b) via Smad activation in mesangial cells. We recently reported that sphingosine 1-phosphate (S1P) induces CTGF expression in rat cultured mesangial cells. However, the mechanism by which S1P induces CTGF expression is unknown. The present study revealed that S1P-induced CTGF expression is mediated via pertussis toxin-insensitive pathways, which are involved in the activation of small GTPases of the Rho family and protein kinase C. We also showed by luciferase reporter assays and chromatin immunoprecipitation that S1P induces CTGF expression via Smad activation as TGF-b does.

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“…Kidney cDNA derived from diseased HIGA mice is enriched in RNA coding for PDGF and endothelial differentiation gene 5, a receptor that is upregulated in response to PDGF [145]. In the same model, a putative drug mixture that inhibits the receptor tyrosine kinase associated with PDGF ameliorated the glomerular disease [146]; further analysis revealed that the active components were specific to the PDGF-B receptor, without influencing other growth factor receptor tyrosine kinases.…”

Section: Growth Factors and Cytokinesmentioning

confidence: 97%

Prospects and Perspectives on IgA Nephropathy from Animal Models

Emancipator

2011

Contributions to Nephrology

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The focus of this chapter is a systematic and critical review of the insights that experimental models have contributed to our understanding of IgA nephropathy (IgAN). We consider the generation of IgA subject to glomerular deposition, the partitioning of IgA between the circulation and glomeruli, the clearance of IgA and complexes containing IgA from the circulation, the 'upstream' effectors of glomerular pathophysiology, the inflammatory mediators that connect intraglomerular stimuli to functional and morphologic effects, and the contribution of animal models to our current understanding of the role that glycosylation of IgA plays in the genesis of IgAN. In each of these subsections, the evidence in favor of each principle or hypothesis is weighed in consideration of other potentially contradictory evidence and relevant issues related to IgAN in patients. The key limitations of each model system are presented, and where possible, reconciliation of discrepant observations are proposed. Subsequently, a synopsis of spontaneous models that do not offer particular mechanistic insights, and a compilation of experimental therapeutic initiatives, are reviewed. In all respects, the discussion of observations in patients or cells in vitro is limited to points where these data impinge upon interpretation of the data derived from the animal models.

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Genomic analysis of a mouse model of immunoglobulin A nephropathy reveals an enhanced PDGF–EDG5 cascade

Cited by 18 publications

References 42 publications

Inhibition of protein kinase CK2 prevents the progression of glomerulonephritis

Inhibition of protein kinase CK2 prevents the progression of glomerulonephritis

Transcriptional regulation of connective tissue growth factor by sphingosine 1‐phosphate in rat cultured mesangial cells

Prospects and Perspectives on IgA Nephropathy from Animal Models

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