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Article ; Online: Glycosphingolipid metabolism and polycystic kidney disease.

Natoli, Thomas A / Modur, Vijay / Ibraghimov-Beskrovnaya, Oxana

2020 Volume 69, Page(s) 109526

Abstract: Sphingolipids and glycosphingolipids are classes of structurally and functionally important lipids that regulate multiple cellular processes, including membrane organization, proliferation, cell cycle regulation, apoptosis, transport, migration, and ... ...

Abstract	Sphingolipids and glycosphingolipids are classes of structurally and functionally important lipids that regulate multiple cellular processes, including membrane organization, proliferation, cell cycle regulation, apoptosis, transport, migration, and inflammatory signalling pathways. Imbalances in sphingolipid levels or subcellular localization result in dysregulated cellular processes and lead to the development and progression of multiple disorders, including polycystic kidney disease. This review will describe metabolic pathways of glycosphingolipids with a focus on the evidence linking glycosphingolipid mediated regulation of cell signalling, lipid microdomains, cilia, and polycystic kidney disease. We will discuss molecular mechanisms of glycosphingolipid dysregulation and their impact on cystogenesis. We will further highlight how modulation of sphingolipid metabolism can be translated into new approaches for the treatment of polycystic kidney disease and describe current clinical studies with glucosylceramide synthase inhibitors in Autosomal Dominant Polycystic Kidney Disease.
MeSH term(s)	Animals ; Cilia/metabolism ; Cilia/pathology ; Cysts/metabolism ; Cysts/pathology ; Glycosphingolipids/metabolism ; Humans ; Kidney/metabolism ; Kidney/pathology ; Polycystic Kidney, Autosomal Dominant/metabolism ; Polycystic Kidney, Autosomal Dominant/pathology ; Signal Transduction
Chemical Substances	Glycosphingolipids
Language	English
Publishing date	2020-01-10
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1002702-6
ISSN	1873-3913 ; 0898-6568
ISSN (online)	1873-3913
ISSN	0898-6568
DOI	10.1016/j.cellsig.2020.109526
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Zs.A 2579: Show issues

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Article ; Online: Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease.

Baccam, Gabriel C / Xie, Jian / Jin, Xin / Park, Hyejung / Wang, Bing / Husson, Hervé / Ibraghimov-Beskrovnaya, Oxana / Huang, Chou-Long

Scientific reports

2022 Volume 12, Issue 1, Page(s) 9340

Abstract: A significant population of patients with chronic kidney disease (CKD) develops cardiac hypertrophy, which can lead to heart failure and sudden cardiac death. Soluble klotho (sKL), the shed ectodomain of the transmembrane protein klotho, protects the ... ...

Abstract	A significant population of patients with chronic kidney disease (CKD) develops cardiac hypertrophy, which can lead to heart failure and sudden cardiac death. Soluble klotho (sKL), the shed ectodomain of the transmembrane protein klotho, protects the heart against hypertrophic growth. We have shown that sKL protects the heart by regulating the formation and function of lipid rafts by targeting the sialic acid moiety of gangliosides, GM1/GM3. Reduction in circulating sKL contributes to an increased risk of cardiac hypertrophy in mice. sKL replacement therapy has been considered but its use is limited by the inability to mass produce the protein. Therefore, alternative methods to protect the heart are proposed. Glucosylation of ceramide catalyzed by glucosylceramide synthase is the entry step for the formation of gangliosides. Here we show that oral administration of a glucosylceramide synthase inhibitor (GCSi) reduces plasma and heart tissue glycosphingolipids, including gangliosides. Administration of GCSi is protective in two mouse models of cardiac stress-induction, one with isoproterenol overstimulation and the other with 5/6 nephrectomy-induced CKD. Treatment with GCSi does not alter the severity of renal dysfunction and hypertension in CKD. These results provide proof of principle for targeting glucosylceramide synthase to decrease gangliosides as a treatment for cardiac hypertrophy. They also support the hypothesis that sKL protects the heart by targeting gangliosides.
MeSH term(s)	Animals ; Cardiomegaly/drug therapy ; Cardiomegaly/prevention & control ; Gangliosides/metabolism ; Glucosyltransferases ; Humans ; Mice ; Renal Insufficiency, Chronic/complications ; Renal Insufficiency, Chronic/drug therapy
Chemical Substances	Gangliosides ; Glucosyltransferases (EC 2.4.1.-) ; ceramide glucosyltransferase (EC 2.4.1.80)
Language	English
Publishing date	2022-06-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-13390-z
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Article: Molecular pathogenesis of ADPKD and development of targeted therapeutic options.

Ibraghimov-Beskrovnaya, Oxana

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

2007 Volume 22, Issue 12, Page(s) 3367–3370

MeSH term(s)	Animals ; Cell Cycle/drug effects ; Cell Cycle/physiology ; Cilia/drug effects ; Cilia/physiology ; Humans ; Polycystic Kidney, Autosomal Dominant/drug therapy ; Polycystic Kidney, Autosomal Dominant/etiology ; Signal Transduction/drug effects
Language	English
Publishing date	2007-12
Publishing country	England
Document type	Editorial ; Review
ZDB-ID	90594-x
ISSN	1460-2385 ; 0931-0509
ISSN (online)	1460-2385
ISSN	0931-0509
DOI	10.1093/ndt/gfm426
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Zs.A 2198: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 329: Show issues

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Article ; Online: Targeting dysregulated cell cycle and apoptosis for polycystic kidney disease therapy.

Ibraghimov-Beskrovnaya, Oxana

Cell cycle (Georgetown, Tex.)

2007 Volume 6, Issue 7, Page(s) 776–779

Abstract: Polycystic kidneys diseases (PKDs) represent a group of disorders characterized by the growth of fluid filled cysts in kidneys and other organs. No effective treatment is currently available for PKDs. A link between dysfunctional cilia and cell cycle ... ...

Abstract	Polycystic kidneys diseases (PKDs) represent a group of disorders characterized by the growth of fluid filled cysts in kidneys and other organs. No effective treatment is currently available for PKDs. A link between dysfunctional cilia and cell cycle regulation has been recently discovered as the most proximal trigger of cystogenesis. We examined the benefit of therapeutic correction of the cell cycle dysregulation in PKD with the cyclin dependent kinase (CDK) inhibitor roscovitine. Our data show that CDK inhibition results in the robust, long lasting arrest of cystogenesis in both slowly progressive and aggressive mouse models of PKD. Dissection of the molecular mechanism of CDK inhibitor action shows effective cell cycle arrest, transcriptional inhibition and attenuation of apoptosis. Roscovitine treatment has proven highly effective in preserving the renal function in treated animals. We also detected significant downregulation of cAMP and aquaporin 2 in treated kidneys, suggesting the effect of CDK inhibition on preservation of epithelial differentiation. CDK inhibition was shown to be efficacious in multiple other types of renal diseases with abnormal cell cycle and proliferation. Thus, therapies directly targeting coordinate regulation of proliferation and apoptosis are emerging as effective approaches to treat multiple renal diseases.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Apoptosis/physiology ; Cell Cycle Proteins/drug effects ; Cell Cycle Proteins/metabolism ; Cell Differentiation/drug effects ; Cell Differentiation/physiology ; Cell Proliferation/drug effects ; Cyclin-Dependent Kinases/antagonists & inhibitors ; Cyclin-Dependent Kinases/metabolism ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Genes, cdc/drug effects ; Genes, cdc/physiology ; Humans ; Mice ; Polycystic Kidney Diseases/drug therapy ; Polycystic Kidney Diseases/enzymology ; Polycystic Kidney Diseases/physiopathology ; Purines/pharmacology ; Purines/therapeutic use ; Roscovitine
Chemical Substances	Cell Cycle Proteins ; Enzyme Inhibitors ; Purines ; Roscovitine (0ES1C2KQ94) ; Cyclin-Dependent Kinases (EC 2.7.11.22)
Language	English
Publishing date	2007-04-21
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.6.7.4047
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Zs.A 5881: Show issues

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Article ; Online: Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models.

Rubel, Diana / Boulanger, Joseph / Craciun, Florin / Xu, Ethan Y / Zhang, Yanqin / Phillips, Lucy / Callahan, Michelle / Weber, William / Song, Wenping / Ngai, Nicholas / Bukanov, Nikolay O / Shi, Xingyi / Hariri, Ali / Husson, Hervé / Ibraghimov-Beskrovnaya, Oxana / Liu, Shiguang / Gross, Oliver

Cells

2022 Volume 11, Issue 4

Abstract: ... ...

Abstract	Col4a3
MeSH term(s)	Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Animals ; Antagomirs ; Collagen Type IV/genetics ; Collagen Type IV/metabolism ; Disease Models, Animal ; Fibrosis ; Humans ; Mice ; Mice, Knockout ; MicroRNAs/antagonists & inhibitors ; Nephritis, Hereditary/drug therapy ; Nephritis, Hereditary/genetics ; Renal Insufficiency/drug therapy
Chemical Substances	Angiotensin-Converting Enzyme Inhibitors ; Antagomirs ; Collagen Type IV ; MIRN21 microRNA, mouse ; MicroRNAs
Language	English
Publishing date	2022-02-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11040594
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Article ; Online: Enhanced exon skipping and prolonged dystrophin restoration achieved by TfR1-targeted delivery of antisense oligonucleotide using FORCE conjugation in mdx mice.

Desjardins, Cody A / Yao, Monica / Hall, John / O'Donnell, Emma / Venkatesan, Reshmii / Spring, Sean / Wen, Aiyun / Hsia, Nelson / Shen, Peiyi / Russo, Ryan / Lan, Bo / Picariello, Tyler / Tang, Kim / Weeden, Timothy / Zanotti, Stefano / Subramanian, Romesh / Ibraghimov-Beskrovnaya, Oxana

Nucleic acids research

2022 Volume 50, Issue 20, Page(s) 11401–11414

Abstract: Current therapies for Duchenne muscular dystrophy (DMD) use phosphorodiamidate morpholino oligomers (PMO) to induce exon skipping in the dystrophin pre-mRNA, enabling the translation of a shortened but functional dystrophin protein. This strategy has ... ...

Abstract	Current therapies for Duchenne muscular dystrophy (DMD) use phosphorodiamidate morpholino oligomers (PMO) to induce exon skipping in the dystrophin pre-mRNA, enabling the translation of a shortened but functional dystrophin protein. This strategy has been hampered by insufficient delivery of PMO to cardiac and skeletal muscle. To overcome these limitations, we developed the FORCETM platform consisting of an antigen-binding fragment, which binds the transferrin receptor 1, conjugated to an oligonucleotide. We demonstrate that a single dose of the mouse-specific FORCE-M23D conjugate enhances muscle delivery of exon skipping PMO (M23D) in mdx mice, achieving dose-dependent and robust exon skipping and durable dystrophin restoration. FORCE-M23D-induced dystrophin expression reached peaks of 51%, 72%, 62%, 90% and 77%, of wild-type levels in quadriceps, tibialis anterior, gastrocnemius, diaphragm, and heart, respectively, with a single 30 mg/kg PMO-equivalent dose. The shortened dystrophin localized to the sarcolemma, indicating expression of a functional protein. Conversely, a single 30 mg/kg dose of unconjugated M23D displayed poor muscle delivery resulting in marginal levels of exon skipping and dystrophin expression. Importantly, FORCE-M23D treatment resulted in improved functional outcomes compared with administration of unconjugated M23D. Our results suggest that FORCE conjugates are a potentially effective approach for the treatment of DMD.
MeSH term(s)	Animals ; Mice ; Dystrophin/genetics ; Exons/genetics ; Mice, Inbred mdx ; Morpholinos/pharmacology ; Muscle, Skeletal/metabolism ; Muscular Dystrophy, Duchenne/genetics ; Muscular Dystrophy, Duchenne/therapy ; Oligonucleotides, Antisense/pharmacology ; Receptors, Transferrin/genetics
Chemical Substances	Dystrophin ; Morpholinos ; Oligonucleotides, Antisense ; Receptors, Transferrin
Language	English
Publishing date	2022-09-29
Publishing country	England
Document type	Journal Article
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkac641
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Zs.A 1067: Show issues

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Article: Polycystic kidney diseases: from molecular discoveries to targeted therapeutic strategies.

Ibraghimov-Beskrovnaya, O / Bukanov, N

Cellular and molecular life sciences : CMLS

2007 Volume 65, Issue 4, Page(s) 605–619

Abstract: Polycystic kidney diseases (PKDs) represent a large group of progressive renal disorders characterized by the development of renal cysts leading to end-stage renal disease. Enormous strides have been made in understanding the pathogenesis of PKDs and the ...

Abstract	Polycystic kidney diseases (PKDs) represent a large group of progressive renal disorders characterized by the development of renal cysts leading to end-stage renal disease. Enormous strides have been made in understanding the pathogenesis of PKDs and the development of new therapies. Studies of autosomal dominant and recessive polycystic kidney diseases converge on molecular mechanisms of cystogenesis, including ciliary abnormalities and intracellular calcium dysregulation, ultimately leading to increased proliferation, apoptosis and dedifferentiation. Here we review the pathobiology of PKD, highlighting recent progress in elucidating common molecular pathways of cystogenesis. We discuss available models and challenges for therapeutic discovery as well as summarize the results from preclinical experimental treatments targeting key disease-specific pathways.
MeSH term(s)	Cell Adhesion ; Cell Cycle/genetics ; Humans ; Kidney Failure, Chronic/epidemiology ; Models, Molecular ; Mutation ; Polycystic Kidney Diseases/complications ; Polycystic Kidney Diseases/genetics ; Polycystic Kidney Diseases/therapy ; Polycystic Kidney, Autosomal Dominant/genetics ; Polycystic Kidney, Autosomal Dominant/therapy ; Protein Conformation ; Receptors, Cell Surface/chemistry ; Receptors, Cell Surface/genetics ; TRPP Cation Channels/chemistry
Chemical Substances	PKHD1 protein, human ; Receptors, Cell Surface ; TRPP Cation Channels ; polycystic kidney disease 1 protein
Language	English
Publishing date	2007-11-02
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-007-7362-x
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Zs.A 195: Show issues

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Article ; Online: mTOR signaling in polycystic kidney disease.

Ibraghimov-Beskrovnaya, Oxana / Natoli, Thomas A

Trends in molecular medicine

2011 Volume 17, Issue 11, Page(s) 625–633

Abstract: Polycystic kidney diseases (PKDs) comprise a large group of genetic disorders characterized by formation of cysts in the kidneys and other organs, ultimately leading to end-stage renal disease. Although PKDs can be caused by mutations in different genes, ...

Abstract	Polycystic kidney diseases (PKDs) comprise a large group of genetic disorders characterized by formation of cysts in the kidneys and other organs, ultimately leading to end-stage renal disease. Although PKDs can be caused by mutations in different genes, they converge on a set of common molecular mechanisms involved in cystogenesis and ciliary dysfunction, and can be qualified as ciliopathies. Recent advances in understanding the mechanisms regulating disease progression have led to the development of new therapies that are being tested in both preclinical and clinical trials. In this article, we briefly review a network of molecular pathways of cystogenesis that are regulated by ciliary functions. We discuss the mTOR pathway in depth, highlighting recent progress in understanding its role in PKD and the current results of clinical trials.
MeSH term(s)	Animals ; Cilia/metabolism ; Cilia/pathology ; Clinical Trials as Topic ; Humans ; Kidney/metabolism ; Kidney/pathology ; Kidney/physiopathology ; Mutation ; Polycystic Kidney Diseases/drug therapy ; Polycystic Kidney Diseases/genetics ; Polycystic Kidney Diseases/metabolism ; Protein Kinases/genetics ; Signal Transduction ; Sirolimus/pharmacology ; Sirolimus/therapeutic use ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/metabolism ; TRPP Cation Channels/genetics
Chemical Substances	TRPP Cation Channels ; polycystic kidney disease 1 protein ; Protein Kinases (EC 2.7.-) ; protein kinase D2 (EC 2.7.1.-) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2011-11
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2036490-8
ISSN	1471-499X ; 1471-4914
ISSN (online)	1471-499X
ISSN	1471-4914
DOI	10.1016/j.molmed.2011.06.003
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Zs.A 4345: Show issues

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Article ; Online: Inhibition of TGF-β Increases Bone Volume and Strength in a Mouse Model of Osteogenesis Imperfecta.

Greene, Benjamin / Russo, Ryan J / Dwyer, Shannon / Malley, Katie / Roberts, Errin / Serrielo, Joseph / Piepenhagen, Peter / Cummings, Sheila / Ryan, Susan / Zarazinski, Christine / Uppuganti, Sasidhar / Bukanov, Nikolai / Nyman, Jeffry S / Cox, Megan K / Liu, Shiguang / Ibraghimov-Beskrovnaya, Oxana / Sabbagh, Yves

JBMR plus

2021 Volume 5, Issue 9, Page(s) e10530

Abstract: Osteogenesis imperfecta (OI), is a genetic disorder of bone fragility caused by mutations in collagen I or proteins involved in collagen processing. Previous studies in mice and human OI bones have shown that excessive activation of TGF-β signaling plays ...

Abstract	Osteogenesis imperfecta (OI), is a genetic disorder of bone fragility caused by mutations in collagen I or proteins involved in collagen processing. Previous studies in mice and human OI bones have shown that excessive activation of TGF-β signaling plays an important role in dominant and recessive OI disease progression. Inhibition of TGF-β signaling with a murine pan-specific TGF-β neutralizing antibody (1D11) was shown to significantly increase trabecular bone volume and long bone strength in mouse models of OI. To investigate the frequency of dosing and dose options of TGF-β neutralizing antibody therapy, we assessed the effect of 1D11 on disease progression in a dominant OI mouse model (
Language	English
Publishing date	2021-08-03
Publishing country	England
Document type	Journal Article
ISSN	2473-4039
ISSN (online)	2473-4039
DOI	10.1002/jbm4.10530
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Article ; Online: Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models

Diana Rubel / Joseph Boulanger / Florin Craciun / Ethan Y. Xu / Yanqin Zhang / Lucy Phillips / Michelle Callahan / William Weber / Wenping Song / Nicholas Ngai / Nikolay O. Bukanov / Xingyi Shi / Ali Hariri / Hervé Husson / Oxana Ibraghimov-Beskrovnaya / Shiguang Liu / Oliver Gross

Cells, Vol 11, Iss 594, p

2022 Volume 594

Abstract: Col4a3 −/− Alport mice serve as an animal model for renal fibrosis. MicroRNA-21 (miR-21) expression has been shown to be increased in the kidneys of Alport syndrome patients. Here, we investigated the nephroprotective effects of Lademirsen anti-miR-21 ... ...

Abstract	Col4a3 −/− Alport mice serve as an animal model for renal fibrosis. MicroRNA-21 (miR-21) expression has been shown to be increased in the kidneys of Alport syndrome patients. Here, we investigated the nephroprotective effects of Lademirsen anti-miR-21 therapy. We used a fast-progressing Col4a3 −/− mouse model with a 129/SvJ background and an intermediate-progressing F1 hybrid mouse model with a mixed genetic background, with angiotensin-converting enzyme inhibitor (ACEi) monotherapy in combination with anti-miR-21 therapy. In the fast-progressing model, the anti miR-21 and ACEi therapies showed an additive effect in the reduction in fibrosis, the decline of proteinuria, the preservation of kidney function and increased survival. In the intermediate-progressing F1 model, the anti-miR-21 and ACEi therapies individually improved kidney pathology. Both also improved kidney function and survival; however, the combination showed a significant additive effect, particularly for survival. RNA sequencing (RNA-seq) gene expression profiling revealed that the anti-miR-21 and ACEi therapies modulate several common pathways. However, anti-miR-21 was particularly effective at normalizing the expression profiles of the genes involved in renal tubulointerstitial injury pathways. In conclusion, significant additive effects were detected for the combination of anti-miR-21 and ACEi therapies on kidney function, pathology and survival in Alport mouse models, as well as a strong differential effect of anti-miR-21 on the renal expression of fibrotic factors. These results support the addition of anti-miR-21 to the current standard of care (ACEi) in ongoing clinical trials in patients with Alport syndrome.
Keywords	nephroprotection ; renal fibrosis ; type IV collagen ; Alport syndrome ; microRNA-21 ; podocytopathies ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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