Identification of dicarbonyl and L-xylulose reductase as a therapeutic target in human chronic kidney disease

Perco, Paul; Ju, Wenjun; Kerschbaum, Julia; Leierer, Johannes; Menon, Rajasree; Zhu, Catherine; Kretzler, Matthias; Mayer, Gert; Rudnicki, Michael

doi:10.1172/jci.insight.128120

Cited by 7 publications

(4 citation statements)

References 62 publications

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“…In humans, a correlation between MGO-derived AGEs and early disease progression was observed in diabetic patients [151], recently confirmed by higher levels of GO and MGO found in T2D patients with DN compared to those without DN [152]. Furthermore, an association study between renoprotective factors and CKD progression has revealed a positive correlation of the dicarbonyl and L-xylulose reductase (DCXR) expression with dicarbonyl stress-detoxifying enzymes [153].…”

Section: Dicarbonyl Stress In Aging-related Diseasesmentioning

confidence: 94%

Dicarbonyl Stress at the Crossroads of Healthy and Unhealthy Aging

Nigro

Leone

Fiory

et al. 2019

Cells

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Dicarbonyl stress occurs when dicarbonyl metabolites (i.e., methylglyoxal, glyoxal and 3-deoxyglucosone) accumulate as a consequence of their increased production and/or decreased detoxification. This toxic condition has been associated with metabolic and age-related diseases, both of which are characterized by a pro-inflammatory and pro-oxidant state. Methylglyoxal (MGO) is the most reactive dicarbonyl and the one with the highest endogenous flux. It is the precursor of the major quantitative advanced glycated products (AGEs) in physiological systems, arginine-derived hydroimidazolones, which accumulate in aging and dysfunctional tissues. The aging process is characterized by a decline in the functional properties of cells, tissues and whole organs, starting from the perturbation of crucial cellular processes, including mitochondrial function, proteostasis and stress-scavenging systems. Increasing studies are corroborating the causal relationship between MGO-derived AGEs and age-related tissue dysfunction, unveiling a previously underestimated role of dicarbonyl stress in determining healthy or unhealthy aging. This review summarizes the latest evidence supporting a causal role of dicarbonyl stress in age-related diseases, including diabetes mellitus, cardiovascular disease and neurodegeneration.

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Section: Dicarbonyl Stress In Aging-related Diseasesmentioning

confidence: 94%

Dicarbonyl Stress at the Crossroads of Healthy and Unhealthy Aging

Nigro

Leone

Fiory

et al. 2019

Cells

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“…A wide range of biomarkers have been identified for the onset of type 1 diabetes ( 14 – 24 ) by INNODIA; for risk prediction ( 14 , 15 , 17 – 21 ) and identification of patients at high-risk of type 2 diabetes ( 25 ) by SUMMIT, IMIDIA, DIRECT, and EMIF; for pancreatic β-cells function and protection by RHAPSODY ( 26 , 27 ) and INNODIA ( 14 , 16 , 22 – 24 ); for hyperglycemia by RHAPSODY ( 28 ); for protection, prediction, initiation, progression, patient stratification, and medicine efficacy of diabetic kidney disease (DKD) ( 29 , 30 ) by SUMMIT and BEAT-DKD ( 31 – 39 ); for development of cardiovascular disease (CVD) by SUMMIT ( 30 , 40 , 41 ); and for the development of diabetic retinopathy (DR) by SUMMIT ( 30 , 42 , 43 ).…”

Section: Resultsmentioning

confidence: 99%

Scientific Advances in Diabetes: The Impact of the Innovative Medicines Initiative

2021

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Diabetes Mellitus is one of the World Health Organization's priority diseases under research by the first and second programmes of Innovative Medicines Initiative, with the acronyms IMI1 and IMI2, respectively. Up to October of 2019, 13 projects were funded by IMI for Diabetes & Metabolic disorders, namely SUMMIT, IMIDIA, DIRECT, StemBANCC, EMIF, EBiSC, INNODIA, RHAPSODY, BEAT-DKD, LITMUS, Hypo-RESOLVE, IM2PACT, and CARDIATEAM. In general, a total of €447 249 438 was spent by IMI in the area of Diabetes. In order to prompt a better integration of achievements between the different projects, we perform a literature review and used three data sources, namely the official project's websites, the contact with the project's coordinators and co-coordinator, and the CORDIS database. From the 662 citations identified, 185 were included. The data collected were integrated into the objectives proposed for the four IMI2 program research axes: (1) target and biomarker identification, (2) innovative clinical trials paradigms, (3) innovative medicines, and (4) patient-tailored adherence programmes. The IMI funded projects identified new biomarkers, medical and research tools, determinants of inter-individual variability, relevant pathways, clinical trial designs, clinical endpoints, therapeutic targets and concepts, pharmacologic agents, large-scale production strategies, and patient-centered predictive models for diabetes and its complications. Taking into account the scientific data produced, we provided a joint vision with strategies for integrating personalized medicine into healthcare practice. The major limitations of this article were the large gap of data in the libraries on the official project websites and even the Cordis database was not complete and up to date.

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“…6). In the vast majority of cases, these proteins are known to play a certain role in the development of cardiovascular pathology [33,[38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53]. The most pronounced decrease in the kidneys of SHR rats was observed in the relative content of renal mitochondrial acyl-CoA medium-chain synthetase-3 (ACSM3) (ACSM3, 0.007 versus 1 in the control, i.e.…”

Section: F1lmg2 Bhmt2mentioning

confidence: 99%

Comparative proteomic analysis of renal tissue of normotensive and hypertensive rats

Buneeva,

Fedchenko,

Kaloshina

et al. 2024

BIOMED KHIM

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Comparative proteomic analysis of kidney tissue from normotensive (WKY) and spontaneously hypertensive (SHR) rats revealed quantitative and qualitative changes in renal proteins. The number of renal proteins specific for WKY rats (blood pressure 110–120 mm Hg) was 13–16. There were 20–24 renal proteins specific for SHR (blood pressure 180 mm Hg and more). The total number of identified renal proteins common for both rat strains included 972–975 proteins. A pairwise comparison of all possible (SHR-WKY) variants identified 8 proteins specific only for normotensive (WKY) animals, and 7 proteins specific only for hypertensive ones (SHR). Taking into consideration their biological roles, the lack of some enzyme proteins in hypertensive rats (for example, biliverdin reductase A) reduces the production of molecules exhibiting antihypertensive properties, while the appearance of others (e.g. betaine-homocysteine S-methyltransferase 2, septin 2, etc.) can be interpreted as a compensatory reaction. Renal proteins with altered relative content (with more than 2.5-fold change) accounted for no more than 5% of all identified proteins. Among the proteins with an increased relative content in hypertensive animals, the largest group consisted of proteins involved in the processes of energy generation and carbohydrate metabolism, as well as antioxidant and protective proteins. In the context of the development of hypertension, the identified relative changes can apparently be considered compensatory. Among the proteins with the most pronounced decrease in the relative content in hypertensive rats, the dramatic reduction in acyl-CoA medium-chain synthetase-3 (ACSM3) appears to make an important contribution to the development of renal pathology in these animals.

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Identification of dicarbonyl and L-xylulose reductase as a therapeutic target in human chronic kidney disease

Cited by 7 publications

References 62 publications

Dicarbonyl Stress at the Crossroads of Healthy and Unhealthy Aging

Dicarbonyl Stress at the Crossroads of Healthy and Unhealthy Aging

Scientific Advances in Diabetes: The Impact of the Innovative Medicines Initiative

Comparative proteomic analysis of renal tissue of normotensive and hypertensive rats

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