Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease

Falkevall, Annelie; Mehlem, Annika; Palombo, Isolde; Sahlgren, Benjamin Heller; Ebarasi, Lwaki; He, Liqun; Ytterberg, A. Jimmy; Olauson, Hannes; Axelsson, Jonas; Sundelin, Birgitta; Patrakka, Jaakko; Scotney, Pierre; Nash, Andrew D.; Eriksson, Ulf

doi:10.1016/j.cmet.2017.01.004

Cited by 132 publications

(116 citation statements)

References 29 publications

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“…Concomitantly, it appears that either too much or too little of VEGFA can lead to pathological changes in the kidney . Interestingly, inhibition of VEGFB signalling in experimental DKD models appears to protect against DKD— via non‐angiogenic mechanisms—by ameliorating renal lipotoxicity and thereby reducing pathological changes in the kidney, sensitizing podocytes to insulin and preventing renal dysfunction …”

Section: Diabetes and Diabetic Kidney Diseasementioning

confidence: 99%

SHIPping out diabetes—Metformin, an old friend among new SHIP2 inhibitors

Lehtonen

2019

Acta Physiologica

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SHIP2 (Src homology 2 domain‐containing inositol 5′‐phosphatase 2) belongs to the family of 5′‐phosphatases. It regulates the phosphoinositide 3‐kinase (PI3K)‐mediated insulin signalling cascade by dephosphorylating the 5′‐position of PtdIns(3,4,5)P3 to generate PtdIns(3,4)P2, suppressing the activity of the pathway. SHIP2 mouse models and genetic studies in human propose that increased expression or activity of SHIP2 contributes to the pathogenesis of the metabolic syndrome, hypertension and type 2 diabetes. This has raised great interest to identify SHIP2 inhibitors that could be used to design new treatments for metabolic diseases. This review summarizes the central mechanisms associated with the development of diabetic kidney disease, including the role of insulin resistance, and then moves on to describe the function of SHIP2 as a regulator of metabolism in mouse models. Finally, the identification of SHIP2 inhibitors and their effects on metabolic processes in vitro and in vivo are outlined. One of the newly identified SHIP2 inhibitors is metformin, the first‐line medication prescribed to patients with type 2 diabetes, further boosting the attraction of SHIP2 as a treatment target to ameliorate metabolic disorders.

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Section: Diabetes and Diabetic Kidney Diseasementioning

confidence: 99%

SHIPping out diabetes—Metformin, an old friend among new SHIP2 inhibitors

Lehtonen

2019

Acta Physiologica

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“…Lipid extracts from circa 3 mg of freeze-dried yeast cells were subjected to UHPLC-MS based lipidomic analysis at Swedish Metabolomics Centre (Umeå, Sweden) as described previously (Falkevall et al, 2017;Mehlem et al, 2016). After a modified Folch extraction (chloroform:methanol 2:1 v/v, including internal standards) (Nygren, Seppänen-Laakso, Castillo, Hyötyläinen, & Orešič, 2011), the extracted lipids were separated on an Acquity UPLC CSH C18 column (2.1 × 50 mm, 1.7 μm) using Agilent 1290 Infinity UHPLC system.…”

Section: Lipidomicsmentioning

confidence: 99%

Modulation of saturation and chain length of fatty acids in Saccharomyces cerevisiae for production of cocoa butter‐like lipids

Bergenholm

Gossing

Wei

et al. 2018

Biotech & Bioengineering

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Chain length and degree of saturation plays an important role for the characteristics of various products derived from fatty acids, such as fuels, cosmetics, and food additives. The seeds of Theobroma cacao are the source of cocoa butter, a natural lipid of high interest for the food and cosmetics industry. Cocoa butter is rich in saturated fatty acids that are stored in the form of triacylglycerides (TAGs). One of the major TAG species of cocoa butter, consisting of two stearic acid molecules and one oleic acid molecule (stearic acid-oleic acid-stearic acid, sn-SOS), is particularly rare in nature as the saturated fatty acid stearic acid is typically found only in low abundance. Demand for cocoa butter is increasing, yet T. cacao can only be cultivated in some parts of the tropics. Alternative means of production of cocoa butter lipids (CBLs) are, therefore, sought after. Yeasts also store fatty acids in the form of TAGs, but these are typically not rich in saturated fatty acids. To make yeast an attractive host for microbial production of CBLs, its fatty acid composition needs to be optimized. We engineered Saccharomyces cerevisiae yeast strains toward a modified fatty acid synthesis. Analysis of the fatty acid profile of the modified strains showed that the fatty acid content as well as the titers of saturated fatty acids and the titers of TAGs were increased. The relative content of potential CBLs in the TAG pool reached up to 22% in our engineered strains, which is a 5.8-fold increase over the wild-type. SOS content reached a level of 9.8% in our engineered strains, which is a 48-fold increase over the wild type.

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“…One-half of diabetic patients develop DKD in their life time (Lingaraj et al 2013;Mohamed et al 2016), making it the major cause of chronic kidney disease and end-stage renal disease (Reidy et al 2014). Early lesions of DKD include glomerular mesangial expansion, extracellular matrix accumulation and proteinuria Falkevall et al 2017;Chen et al 2018). Studies suggest DKD may result from a combinational change of genetics, metabolism, environment and life style; however, its exact underlying mechanisms remain not fully understood (Lingaraj et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

Hong

Huang

Xiu-qin

et al. 2018

The Journal of Physiology

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Key points Diabetic kidney disease (DKD) is a major complication of diabetes. We found that UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase, was upregulated in the renal mesangial and tubular cells of diabetic mice and DKD patients. In cultured renal mesangial and tubular cells, UTX overexpression promoted palmitic acid‐induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. We found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes and apoptosis; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal abnormalities in db/db mice, an animal model of type 2 diabetes. These results revealed the possible mechanisms underlying the regulation of histone methylation in DKD and suggest UTX as a potential therapeutic target for DKD. Abstract Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the leading cause of end‐stage kidney disease worldwide without effective therapy available. UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase that removes the di‐ and tri‐methyl groups from histone H3K27, plays important biological roles in gene activation, cell fate control and life span regulation in Caenorhabditis elegans. In the present study, we report upregulated UTX in the kidneys of diabetic mice and DKD patients. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal dysfunction, abnormal morphology, inflammation, apoptosis and DNA damage in db/db mice, comprising an animal model of type 2 diabetes. In cultured renal mesanglial and tubular cells, UTX overexpression promoted palmitic acid induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. Mechanistically, we found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Collectively, our results suggest UTX as a potential therapeutic target for DKD.

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Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease

Cited by 132 publications

References 29 publications

SHIPping out diabetes—Metformin, an old friend among new SHIP2 inhibitors

SHIPping out diabetes—Metformin, an old friend among new SHIP2 inhibitors

Modulation of saturation and chain length of fatty acids in Saccharomyces cerevisiae for production of cocoa butter‐like lipids

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

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