SRPK1 inhibition <i>in vivo</i>: modulation of VEGF splicing and potential treatment for multiple diseases

Oltean, Sebastian; Gammons, Melissa V.; Hulse, Richard P.; Hamdollah-Zadeh, Maryam; Mavrou, Athina; Donaldson, Lucy F.; Salmon, Andrew; Harper, Steven J.; Ladomery, Michael; Bates, David O.

doi:10.1042/bst20120051

Cited by 49 publications

(48 citation statements)

References 44 publications

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“…25 We show here that diabetic patients with well preserved kidney function have increased VEGF-A 165 b levels relative to VEGF-A 165 a. Transgenic podocyte-specific VEGF-A 165 b overexpression is the most analogous experimental model of this human situation, and it is noteworthy that the local upregulation of VEGF-A 165 b was the most effective approach in preventing multiple physiologic and histologic changes of diabetic nephropathy. We hypothesize that patients capable of upregulating VEGF-A 165 b relative to VEGF-A 165 a, via the modifiable machinery that regulates alternative splicing of the VEGF-A gene, 23,[26][27][28][29] may be protected from progressive nephropathy in diabetes. How to manipulate this alternative splicing mechanism for therapeutic benefit requires further exploration.…”

Section: Discussionmentioning

confidence: 99%

Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy

Oltean¹,

Qiu²,

Ferguson³

et al. 2015

Journal of the American Society of Nephrology

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118

166

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Diabetic nephropathy is the leading cause of ESRD in high-income countries and a growing problem across the world. Vascular endothelial growth factor-A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in diabetic nephropathy, yet VEGF-A knockout and overexpression of angiogenic VEGF-A isoforms each worsen diabetic nephropathy. We examined the vasculoprotective effects of the VEGF-A isoform VEGF-A 165 b in diabetic nephropathy. Renal expression of VEGF-A 165 b mRNA was upregulated in diabetic individuals with well preserved kidney function, but not in those with progressive disease. Reproducing this VEGF-A 165 b upregulation in mouse podocytes in vivo prevented functional and histologic abnormalities in diabetic nephropathy. Biweekly systemic injections of recombinant human VEGF-A 165 b reduced features of diabetic nephropathy when initiated during early or advanced nephropathy in a model of type 1 diabetes and when initiated during early nephropathy in a model of type 2 diabetes. VEGF-A 165 b normalized glomerular permeability through phosphorylation of VEGF receptor 2 in glomerular endothelial cells, and reversed diabetes-induced damage to the glomerular endothelial glycocalyx. VEGF-A 165 b also improved the permeability function of isolated diabetic human glomeruli. These results show that VEGF-A 165 b acts via the endothelium to protect blood vessels and ameliorate diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy

Oltean¹,

Qiu²,

Ferguson³

et al. 2015

Journal of the American Society of Nephrology

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118

166

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“…[26][27][28] Several studies have shown the involvement of various members of splicing kinases, especially SRPKs in multiple cellular processes including proliferation and angiogenesis. 29,30 Overexpression of splicing factors (SRSF1, SRSF2) has been reported in lung, colon and breast cancers.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of splicing proteins in head and neck squamous cell carcinoma

Radhakrishnan

Nanjappa

Raja

et al. 2016

Cancer Biology & Therapy

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ABSRTRACTSignaling plays an important role in regulating all cellular pathways. Altered signaling is one of the hallmarks of cancers. Phosphoproteomics enables interrogation of kinase mediated signaling pathways in biological systems. In cancers, this approach can be utilized to identify aberrantly activated pathways that potentially drive proliferation and tumorigenesis. To identify signaling alterations in head and neck squamous cell carcinoma (HNSCC), we carried out proteomic and phosphoproteomic analysis of HNSCC cell lines using a combination of tandem mass tag (TMT) labeling approach and titanium dioxide-based enrichment. We identified 4,920 phosphosites corresponding to 2,212 proteins in six HNSCC cell lines compared to a normal oral cell line. Our data indicated significant enrichment of proteins associated with splicing. We observed hyperphosphorylation of SRSF protein kinase 2 (SRPK2) and its downstream substrates in HNSCC cell lines. SRPK2 is a splicing kinase, known to phosphorylate serine/arginine (SR) rich domain proteins and regulate splicing process in eukaryotes. Although genome-wide studies have reported the contribution of alternative splicing events of several genes in the progression of cancer, the involvement of splicing kinases in HNSCC is not known. In this study, we studied the role of SRPK2 in HNSCC. Inhibition of SRPK2 resulted in significant decrease in colony forming and invasive ability in a panel of HNSCC cell lines. Our results indicate that phosphorylation of SRPK2 plays a crucial role in the regulation of splicing process in HNSCC and that splicing kinases can be developed as a new class of therapeutic target in HNSCC.

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“…54,55 The lower availability results in alterations in AS of specific genes regulated by MBNL, which contribute to myotonic dystrophy pathogenesis. SRPK1, a kinase that phosphorylates SR-proteins (the class of splice factors mentioned above), is overexpressed in several cancers [56][57][58] and also in DenysDrash syndrome, associated renal failure, and increased incidence of Wilms tumors. 59 SRPK1 is a determinant of angiogenesis through modulation of VEGF-A splicing and its abnormal expression maintains a pathologic loop by promoting proangiogenic and propermeability VEGF-A isoforms.…”

Section: Splice Factors or Splicing-specific Kinases Are Deregulated mentioning

confidence: 99%

Alternative Splicing in CKD

Stevens

Oltean

2016

JASN

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Alternative splicing (AS) has emerged in the postgenomic era as one of the main drivers of proteome diversity, with $94% of multiexon genes alternatively spliced in humans. AS is therefore one of the main control mechanisms for cell phenotype, and is a process deregulated in disease. Numerous reports describe pathogenic mutations in splice factors, splice sites, or regulatory sequences. Additionally, compared with the physiologic state, disease often associates with an abnormal proportion of splice isoforms (or novel isoforms), without an apparent driver mutation. It is therefore essential to study how AS is regulated in physiology, how it contributes to pathogenesis, and whether we can manipulate faulty splicing for therapeutic advantage. Although the disease most commonly linked to deregulation of AS in several genes is cancer, many reports detail pathogenic splice variants in diseases ranging from neuromuscular disorders to diabetes or cardiomyopathies. A plethora of splice variants have been implicated in CKDs as well. In this review, we describe examples of these CKD-associated splice variants and ideas on how to manipulate them for therapeutic benefit.

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SRPK1 inhibition in vivo: modulation of VEGF splicing and potential treatment for multiple diseases

Cited by 49 publications

References 44 publications

Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy

Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy

Dysregulation of splicing proteins in head and neck squamous cell carcinoma

Alternative Splicing in CKD

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