Novel reno-protective mechanism of Aspirin involves H2AK119 monoubiquitination and Set7 in preventing type 1 diabetic nephropathy

Goru, Santosh Kumar; Gaikwad, Anil Bhanudas

doi:10.1016/j.pharep.2017.11.018

Cited by 14 publications

(6 citation statements)

References 41 publications

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“…Experimental inhibition of Set7/NF-kB inflammatory signalling has obtained with Quercus infectoria in bone marrow-derived macrophages exposed to a diabetic environment [150]. Histone H2AK119 mono-ubiquitination (H2AK119-Ub) has a key role in regulating Set7 activity; accordingly, lower levels of Set7 and prevention of renal fibrosis have been correlated to increased protein expression of H2AK119-Ub in response to aspirin in glomeruli from diabetic animals [151]. Although very preliminary, these observations will hopefully contribute to add new options to the list of therapeutic targets for diabetes vascular complications.…”

Section: Epigenetic Mechanisms As Potential Therapeutic Targets Inmentioning

confidence: 99%

Can Epigenetics of Endothelial Dysfunction Represent the Key to Precision Medicine in Type 2 Diabetes Mellitus?

Coco

Sgarra

Potenza

et al. 2019

IJMS

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In both developing and industrialized Countries, the growing prevalence of Type 2 Diabetes Mellitus (T2DM) and the severity of its related complications make T2DM one of the most challenging metabolic diseases worldwide. The close relationship between genetic and environmental factors suggests that eating habits and unhealthy lifestyles may significantly affect metabolic pathways, resulting in dynamic modifications of chromatin-associated proteins and homeostatic transcriptional responses involved in the progression of T2DM. Epigenetic mechanisms may be implicated in the complex processes linking environmental factors to genetic predisposition to metabolic disturbances, leading to obesity and type 2 diabetes mellitus (T2DM). Endothelial dysfunction represents an earlier marker and an important player in the development of this disease. Dysregulation of the endothelial ability to produce and release vasoactive mediators is recognized as the initial feature of impaired vascular activity under obesity and other insulin resistance conditions and undoubtedly concurs to the accelerated progression of atherosclerotic lesions and overall cardiovascular risk in T2DM patients. This review aims to summarize the most current knowledge regarding the involvement of epigenetic changes associated with endothelial dysfunction in T2DM, in order to identify potential targets that might contribute to pursuing “precision medicine” in the context of diabetic illness.

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Section: Epigenetic Mechanisms As Potential Therapeutic Targets Inmentioning

confidence: 99%

Can Epigenetics of Endothelial Dysfunction Represent the Key to Precision Medicine in Type 2 Diabetes Mellitus?

Coco

Sgarra

Potenza

et al. 2019

IJMS

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“…20,21 Ubiquitination, as a part of the is a post-translational modification that an important influence on the pathogenesis of DN. 22,23 The UPS is accountable for proteasome-mediated intracellular protein degradation or alterations in cellular signaling pathways. Given the significance of modification omics in detecting ubiquitinated proteins and their locations, we ascertained the ubiquitylome in the kidney tissue of mice with type 2 DN.…”

Section: Discussionmentioning

confidence: 99%

c‐Cbl induced podocin ubiquitination contributes to the podocytes injury in diabetic nephropathy

Liang,

He,

Zhou

et al. 2024

The FASEB Journal

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The ubiquitination function in diabetic nephropathy (DN) has attracted much attention, but there is a lack of information on its ubiquitylome profile. To examine the differences in protein content and ubiquitination in the kidney between db/db mice and db/m mice, we deployed liquid chromatography‐mass spectrometry (LC–MS/MS) to conduct analysis. We determined 145 sites in 86 upregulated modified proteins and 66 sites in 49 downregulated modified proteins at the ubiquitinated level. Moreover, 347 sites among the 319 modified proteins were present only in the db/db mouse kidneys, while 213 sites among the 199 modified proteins were present only in the db/m mouse kidneys. The subcellular localization study indicated that the cytoplasm had the highest proportion of ubiquitinated proteins (31.87%), followed by the nucleus (30.24%) and the plasma membrane (20.33%). The enrichment analysis revealed that the ubiquitinated proteins are mostly linked to tight junctions, oxidative phosphorylation, and thermogenesis. Podocin, as a typical protein of slit diaphragm, whose loss is a crucial cause of proteinuria in DN. Consistent with the results of ubiquitination omics, the K261R mutant of podocin induced the weakest ubiquitination compared with the K301R and K370R mutants. As an E3 ligase, c‐Cbl binds to podocin, and the regulation of c‐Cbl can impact the ubiquitination of podocin. In conclusion, in DN, podocin ubiquitination contributes to podocyte injury, and K261R is the most significant site. c‐Cbl participates in podocin ubiquitination and may be a direct target for preserving the integrity of the slit diaphragm structure, hence reducing proteinuria in DN.

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“…Of note, the CDK inhibitor roscovitine was shown to promote apoptosis of neutrophils and enhance resolution of inflammation, indicating crosstalk between both mechanisms ( Rossi et al, 2006 ). Additional progress can be gained from repurposing of medication approved for other fibrotic kidney diseases, for example COX inhibitors which have shown potential in the prevention of diabetic nephropathy in addition to ameliorating NPH in rodent models ( Goru, 2018 ).…”

Section: Developments and Future Directionsmentioning

confidence: 99%

Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis

Stokman

Saunier

Benmerah

2021

Front. Cell Dev. Biol.

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Nephronophthisis (NPH) is an autosomal recessive ciliopathy and a major cause of end-stage renal disease in children. The main forms, juvenile and adult NPH, are characterized by tubulointerstitial fibrosis whereas the infantile form is more severe and characterized by cysts. NPH is caused by mutations in over 20 different genes, most of which encode components of the primary cilium, an organelle in which important cellular signaling pathways converge. Ciliary signal transduction plays a critical role in kidney development and tissue homeostasis, and disruption of ciliary signaling has been associated with cyst formation, epithelial cell dedifferentiation and kidney function decline. Drugs have been identified that target specific signaling pathways (for example cAMP/PKA, Hedgehog, and mTOR pathways) and rescue NPH phenotypes in in vitro and/or in vivo models. Despite identification of numerous candidate drugs in rodent models, there has been a lack of clinical trials and there is currently no therapy that halts disease progression in NPH patients. This review covers the most important findings of therapeutic approaches in NPH model systems to date, including hypothesis-driven therapies and untargeted drug screens, approached from the pathophysiology of NPH. Importantly, most animal models used in these studies represent the cystic infantile form of NPH, which is less prevalent than the juvenile form. It appears therefore important to develop new models relevant for juvenile/adult NPH. Alternative non-orthologous animal models and developments in patient-based in vitro model systems are discussed, as well as future directions in personalized therapy for NPH.

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Novel reno-protective mechanism of Aspirin involves H2AK119 monoubiquitination and Set7 in preventing type 1 diabetic nephropathy

Cited by 14 publications

References 41 publications

Can Epigenetics of Endothelial Dysfunction Represent the Key to Precision Medicine in Type 2 Diabetes Mellitus?

Can Epigenetics of Endothelial Dysfunction Represent the Key to Precision Medicine in Type 2 Diabetes Mellitus?

c‐Cbl induced podocin ubiquitination contributes to the podocytes injury in diabetic nephropathy

Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis

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