The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation

He, Jun; Gao, Haoxue; Yang, Na; Zhu, Xiaodong; Sun, Runbin; Xie, Yuan; Zhang, Jingwei; Wang, Jiankun; Ding, Fei; Aa, Jiye; Wang, Guangji

doi:10.1038/s41401-018-0043-5

Cited by 52 publications

(25 citation statements)

References 61 publications

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“…Taking into consideration the aforementioned pathways and the classification of genes based on biological role indicated the important role played by the renin–angiotensin system [ 37 ], angiogenesis and erythropoiesis [ 38 ], lipid metabolism [ 39 ], polyol pathway [ 40 ], inflammatory mechanisms [ 36 , 41 ], oxidative stress [ 42 ], endothelium function [ 43 ] and extracellular matrix degradation [ 44 ], as well as epigenetic mechanisms [ 45 ] and glucose transport [ 46 , 47 ]. Functional studies remain necessary to confirm the involvement of these mechanisms, in order to clarify the exact role of these polymorphisms and pathways in DN.…”

Section: Discussionmentioning

confidence: 99%

The genetic map of diabetic nephropathy: evidence from a systematic review and meta-analysis of genetic association studies

Tziastoudi

Stefanidis

Ζιντζαράς

2020

Clinical Kidney Journal

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Despite the extensive efforts of scientists, the genetic background of diabetic nephropathy (DN) has not yet been clarified. To elucidate the genetic variants that predispose to the development of DN, we conducted a systematic review and meta-analysis of all available genetic association studies (GAS) of DN. We searched in the Human Genome Epidemiology Navigator (HuGE Navigator) and PubMed for available GAS of DN. The threshold for meta-analysis was three studies per genetic variant. The association between genotype distribution and DN was examined using the generalized linear odds ratio (ORG). For variants with available allele frequencies, the examined model was the allele contrast. The pooled OR was estimated using the DerSimonian and Laird random effects model. The publication bias was assessed with Egger’s test. We performed pathway analysis of significant genes with DAVID 6.7. Genetic data of 606 variants located in 228 genes were retrieved from 360 GASs and were synthesized with meta-analytic methods. ACACB, angiotensin I-converting enzyme (ACE), ADIPOQ, AGT, AGTR1, AKR1B1, APOC1, APOE, ATP1B2, ATP2A3, CARS, CCR5, CGNL1, Carnosine dipeptidase 1 (CNDP1), CYGB-PRCD, EDN1, Engulfment and cell motility 1 (ELMO1), ENPP1, EPO, FLT4, FTO, GLO1, HMGA2, IGF2/INS/TH cluster, interleukin 1B (IL1B), IL8, IL10, KCNQ1, KNG, LOC101927627, Methylenetetrahydrofolate reductase, nitric oxide synthase 3 (NOS3), SET domain containing seven, histone lysine methyltransferase (SETD7), Sirtuin 1 (SIRT1), SLC2A1, SLC2A2, SLC12A3, SLC19A3, TCF7L2, TGFB1, TIMP1, TTC39C, UNC13B, VEGFA, WTAPP1, WWC1 as well as XYLT1 and three intergenic polymorphisms showed significant association with DN. Pathway analysis revealed the overrepresentation of six signalling pathways. The significant findings provide further evidence for genetic factors implication in DN offering new perspectives in discovery of new therapies.

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Section: Discussionmentioning

confidence: 99%

The genetic map of diabetic nephropathy: evidence from a systematic review and meta-analysis of genetic association studies

Tziastoudi

Stefanidis

Ζιντζαράς

2020

Clinical Kidney Journal

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“…A 100 μL aliquot of the supernatant was dried. The following process was performed with the previously described GC-MS conditions for metabolomic analysis [ 18 ]. In brief, the temperature was initially set at 100 °C for 5 min and then increased to 300 °C over 25 min.…”

Section: Methodsmentioning

confidence: 99%

Rebalancing of the gut flora and microbial metabolism is responsible for the anti-arthritis effect of kaempferol

Fei

et al. 2019

Acta Pharmacol Sin

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Kaempferol is a natural flavonol that possesses various pharmacological activities, including anti-arthritis effects, yet the underlying mechanisms remain controversial. To evaluate the anti-arthritis efficacy and the underlying mechanisms of kaempferol, collagen-induced arthritis (CIA) mice were treated with kaempferol intragastrically (200 mg · kg −1 · d −1 ) and intraperitoneally (20 mg · kg −1 · d −1 ). Pharmacodynamic and pharmacokinetic studies showed that the oral administration of kaempferol produced distinct anti-arthritis effects in model mice with arthritis in terms of the spleen index, arthritis index, paw thickness, and inflammatory factors; the bioavailability (1.5%, relative to that of the intraperitoneal injection) and circulatory exposure of kaempferol ( C max = 0.23 ± 0.06 ng/mL) and its primary metabolite kaempferol-3- O -glucuronide ( C max = 233.29 ± 89.64 ng/mL) were rather low. In contrast, the intraperitoneal injection of kaempferol caused marginal anti-arthritis effects, although it achieved a much higher in vivo exposure. The much higher kaempferol content in the gut implicated a potential mechanism involved in the gut. Analysis of 16S ribosomal RNA revealed that CIA caused imbalance of 14 types of bacteria at the family level, whereas kaempferol largely rebalanced the intestinal microbiota in CIA mice. A metabolomics study showed that kaempferol treatment significantly reversed the perturbation of metabolites involved in energy production and the tryptophan, fatty acid and secondary bile acid metabolisms in the gut contents of the CIA mice. In conclusion, we demonstrate for the first time that the high level of kaempferol in the gut regulates the intestinal flora and microbiotic metabolism, which are potentially responsible for the anti-arthritis activities of kaempferol.

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“…The fact that AR inhibitor treatment can prevent the development of DKD highlights the significance of the polyol pathway in the biology of DKD. For example, epalrestat, an inhibitor of AR, can attenuate albuminuria, podocyte foot process fusion, and interstitial fibrosis in type 2 diabetic db/db mice [16]. Moreover, AR-deficient mice are resistant to the progression of diabetic kidney injury [17].…”

Section: The Polyol Pathwaymentioning

confidence: 99%

Targeting Redox Imbalance as an Approach for Diabetic Kidney Disease

et al. 2020

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Diabetic kidney disease (DKD) is a worldwide public health problem. It is the leading cause of end-stage renal disease and is associated with increased mortality from cardiovascular complications. The tight interactions between redox imbalance and the development of DKD are becoming increasingly evident. Numerous cascades, including the polyol and hexosamine pathways have been implicated in the oxidative stress of diabetes patients. However, the precise molecular mechanism by which oxidative stress affects the progression of DKD remains to be elucidated. Given the limited therapeutic options for DKD, it is essential to understand how oxidants and antioxidants are controlled in diabetes and how oxidative stress impacts the progression of renal damage. This review aims to provide an overview of the current status of knowledge regarding the pathological roles of oxidative stress in DKD. Finally, we summarize recent therapeutic approaches to preventing DKD with a focus on the anti-oxidative effects of newly developed anti-hyperglycemic agents.

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The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation

Cited by 52 publications

References 61 publications

The genetic map of diabetic nephropathy: evidence from a systematic review and meta-analysis of genetic association studies

The genetic map of diabetic nephropathy: evidence from a systematic review and meta-analysis of genetic association studies

Rebalancing of the gut flora and microbial metabolism is responsible for the anti-arthritis effect of kaempferol

Targeting Redox Imbalance as an Approach for Diabetic Kidney Disease

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