Spiegelmer Inhibition of CCL2/MCP-1 Ameliorates Lupus Nephritis in MRL-(Fas)lpr Mice

Kulkarni, Onkar P.; Pawar, Rahul D.; Purschke, Werner G.; Eulberg, Dirk; Selve, Norma; Buchner, Klaus; Ninichuk, Volha; Segerer, Stephan; Vielhauer, Volker; Klussmann, Sven; Anders, Hans‐Joachim

doi:10.1681/asn.2006121348

Cited by 168 publications

(135 citation statements)

References 29 publications

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“…Covalent modifications of histone residues determine chromatin structure dynamics and transcription factor accessibility, i.e. epigenetic control of chromatin replication and gene transcription [5,13]. Not much is known about histone epigenetics in diabetes but a recent study suggested that high glucose levels activate the histone acetylases CBP and p/CAF to increase H3 acetylation which in turn leads to an elevated transcription of inflammatory genes in cultured monocytes [16].…”

Section: Discussionmentioning

confidence: 99%

“…The accessibility of chromatin transcription factor binding sites is determined by the position and compaction of histones, proteins that wind up the double-stranded DNA in nucleosomes. Whether the nucleosomes are packed in the chromatin more or less tightly is determined by the activity of a number of enzymes that regulate the covalent modification of distinct amino acids in histones through processes such as acetylation, methylation and phosphorylation [3,13]. For example, histone H3 acetylation at lysines 9, 14, 18 and 23 or mono-or dimethylation at lysine activate chro-matin for transcription factor binding while histone H3 dior trimethylation at lysines 9 and 27 rather silence chromatin by inhibiting transcription factor accessibility [32].…”

Section: Introductionmentioning

confidence: 99%

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Progressive glomerulosclerosis in type 2 diabetes is associated with renal histone H3K9 and H3K23 acetylation, H3K4 dimethylation and phosphorylation at serine 10

Sayyed

Gaikwad

Lichtnekert

et al. 2010

Nephrology Dialysis Transplantation

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Background. Distinct histone modifications regulate gene expression in certain diseases but little is known about histone epigenetics in diabetic nephropathy. The current study examined the role of histone epigenetics in development and progression of nephropathy in db/db mice. Methods. We studied kidney damage in 6-month-old nondiabetic mice and type 2 diabetic db/db mice that underwent either sham surgery or uninephrectomy at 6 weeks of age which accelerates glomerulosclerosis in db/db mice via glomerular hyperfiltration. Histone H3K9 and H3K23 acetylation, H3K4 and H3K9 dimethylation and H3 phosphorylation at serine 10 was explored by western blotting of renal histone extracts. Results. Uninephrectomy in C57BL/6 mice or onset of diabetes in type 2 diabetes reduced renal H3K23 acetylation, H3K4 dimethylation and H3 phosphorylation at serine 10. In contrast, H3K9 and H3K23 acetylation, H3K4 dimethylation and H3 phosphorylation at serine 10 were significantly increased in uninephrectomized db/db mice. The disease pattern of these mice is characterized by an increased glomerular cell proliferation, severe glomerulosclerosis, albuminuria and glomerular filtration rate reduction. Treating uninephrectomized db/db mice with a Mcp-1/Ccl2 antagonist prevented the histopathological damage and the aforementioned histone modification abnormalities of advanced diabetic glomerulosclerosis. Conclusion. We conclude that advanced diabetic nephropathy is associated with increased renal H3K9 and H3K23 acetylation, H3K4 dimethylation and H3 phosphorylation at serine 10 that enhance chromatin unfolding and gene expression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Progressive glomerulosclerosis in type 2 diabetes is associated with renal histone H3K9 and H3K23 acetylation, H3K4 dimethylation and phosphorylation at serine 10

Sayyed

Gaikwad

Lichtnekert

et al. 2010

Nephrology Dialysis Transplantation

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“…24 The members of the chemokine family specifically direct different leukocyte subsets by distinct chemokine receptors into different renal compartments. 63 For example, the chemokine CCL2 recruits CCR2 + proinflammatory macrophages and T cells into the glomerulus and the tubulointerstitium, 64,65 whereas CCR1 + cells only recruit to the interstitial compartment and not to the glomerulus in LN. 66 Other leukocyte subsets involve other chemokines and chemokine receptors for their recruitment into the kidney.…”

Section: Intrarenal Pathogenic Mechanisms Of Lnmentioning

confidence: 99%

The Pathogenesis of Lupus Nephritis

Lech¹,

Anders

2013

Journal of the American Society of Nephrology

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Lupus nephritis is an immune complex GN that develops as a frequent complication of SLE. The pathogenesis of lupus nephritis involves a variety of pathogenic mechanisms. The extrarenal etiology of systemic lupus is based on multiple combinations of genetic variants that compromise those mechanisms normally assuring immune tolerance to nuclear autoantigens. This loss of tolerance becomes clinically detectable by the presence of antinuclear antibodies. In addition, nucleic acids released from netting or apoptotic neutrophils activate innate and adaptive immunity via viral nucleic acid-specific Toll-like receptors. Therefore, many clinical manifestations of systemic lupus resemble those of viral infection. In lupus, endogenous nuclear particles trigger IFN-a signaling just like viral particles during viral infection. As such, dendritic cells, T helper cells, B cells, and plasma cells all contribute to the aberrant polyclonal autoimmunity. The intrarenal etiology of lupus nephritis involves antibody binding to multiple intrarenal autoantigens rather than the deposition of circulating immune complexes. Tertiary lymphoid tissue formation and local antibody production add to intrarenal complement activation as renal immunopathology progresses. Here we provide an update on the pathogenic mechanisms that lead to lupus nephritis and provide the rationale for the latest and novel treatment strategies.

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“…Spiegelmer antagonists to a number of extracellular targets have been described (11,14,24,35). Two Spiegelmers have proven to be safe and well tolerated in Phase I clinical studies 4 providing evidence that the Spiegelmer technology is suitable to generate human medicines.…”

Section: Discussionmentioning

confidence: 99%

Polyetheylenimine-Polyplexes of Spiegelmer NOX-A50 Directed against Intracellular High Mobility Group Protein A1 (HMGA1) Reduce Tumor Growth in Vivo

Maasch¹,

Vater²,

Purschke

et al. 2010

Journal of Biological Chemistry

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High mobility group A1 (HMGA1) proteins belong to a group of architectural transcription factors that are overexpressed in a range of human malignancies, including pancreatic adenocarcinoma. They promote anchorage-independent growth and epithelial-mesenchymal transition and are therefore suggested as potential therapeutic targets. Employing in vitro selection techniques against a chosen fragment of HMGA1, we have generated biostable L-RNA oligonucleotides, so-called Spiegelmers, that specifically bind HMGA1b with low nanomolar affinity. We demonstrate that the best binding Spiegelmers, NOX-A50 and NOX-f33, compete HMGA1b from binding to its natural binding partner, AT-rich doublestranded DNA. We describe a formulation method based on polyplex formation with branched polyethylenimine for efficient delivery of polyethylene glycol-modified Spiegelmers and show improved tissue distribution and persistence in mice. In a xenograft mouse study using the pancreatic cancer cell line PSN-1, subcutaneous administration of 2 mg/kg per day NOX-A50 formulated in polyplexes showed an enhanced delivery of NOX-A50 to the tumor and a significant reduction of tumor volume. Our results demonstrate that intracellular targets can be successfully addressed with a Spiegelmer using polyethylenimine-based delivery and underline the importance of HMGA1 as a therapeutic target in pancreatic cancer.The mammalian nonhistone chromatin high mobility group A1 proteins HMGA1a, 3 HMGA1b, and HMGA1c belong to one protein family encoded by the HMGA1 gene. They act as architectural transcription factors by binding via AT hook motifs to the minor groove of AT-rich DNA, leading to modulation of chromatin and nucleosome remodeling. Their ability to regulate the activity of several genes through the recognition and alteration of the DNA double helix and chromatin substrates has been linked to the development of human cancers (1-3). The overexpression of HMGA proteins is associated with different types of tumors, e.g. pancreas, breast, prostate, cervical, gastric, colorectal cancer as well as lymphomas and neuroblastic malignancies (4 -6). The level of expression of HMGA1a/b is low or almost undetectable in most differentiated or nonproliferating normal cells (7-9) but is rapidly up-regulated in response to growth-stimulatory factors (8, 10). Thus, HMGA1 is considered a promising target to treat cancer development, progression, and metastasis.The aim of our study was to evaluate whether the intracellular HMGA1 protein family can be successfully targeted with a Spiegelmer, a large structured molecule that is comparable with a monoclonal antibody in terms of specific target binding. Spiegelmers (German: Spiegel ϭ mirror) are structured biostable L-oligonucleotides that differ from their aptamer counterparts in their sugar moiety, which consists of mirrorimage L-(deoxy)ribose rather than D-(deoxy)ribose and makes Spiegelmers highly resistant to nucleases (11,12). Spiegelmers have already been described to act potently as inhibitors in vivo (13-15) and have ...

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Spiegelmer Inhibition of CCL2/MCP-1 Ameliorates Lupus Nephritis in MRL-(Fas)lpr Mice

Cited by 168 publications

References 29 publications

Progressive glomerulosclerosis in type 2 diabetes is associated with renal histone H3K9 and H3K23 acetylation, H3K4 dimethylation and phosphorylation at serine 10

Progressive glomerulosclerosis in type 2 diabetes is associated with renal histone H3K9 and H3K23 acetylation, H3K4 dimethylation and phosphorylation at serine 10

The Pathogenesis of Lupus Nephritis

Polyetheylenimine-Polyplexes of Spiegelmer NOX-A50 Directed against Intracellular High Mobility Group Protein A1 (HMGA1) Reduce Tumor Growth in Vivo

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