Renal depletion of<i>myo</i>-inositol is associated with its increased degradation in animal models of metabolic disease

Chang, Hao-Han; Chao, Hsiang-Ning; Walker, Christopher S.; Choong, Soon Y.; Phillips, Anthony R. J.; Loomes, Kerry M.

doi:10.1152/ajprenal.00164.2015

Cited by 31 publications

(35 citation statements)

References 38 publications

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“…Additionally, a substantial amount of sorbitol and fructose was produced as a consequence, and a certain amount of myo-inositol intake was suppressed in multiple organs/tissues, including the renal cortex. Studies showed that the depletion of myo-inositol in turn reduced sodium-potassium adenosine triphosphate activity and altered the cellular metabolism and membrane structure of the cells [39], which were observed in the renal cortex of STZ-diabetic rats [15,16]. It was suggested that the depletion of myo-inositol in the renal cortex contributed to the nephric pathology and dysfunction [40].…”

Section: Discussionmentioning

confidence: 99%

“…Except for diabetes neuropathy, recent accumulative evidence has suggested the potential application of ARIs for renal protection in DN [12,13]. Li et al [14] observed significant depletion of myoinositol in the renal cortex of diabetic kidneys in db/db mice, which is observed in other animal models [15,16]. It has been suggested that the activation of the polyol pathway and AR caused elevated sorbitol levels, osmotic stress of renal cells, and depletion of myo-inositol.…”

Section: Introductionmentioning

confidence: 99%

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

Gao

Yang

et al. 2018

Acta Pharmacol Sin

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Epalrestat is an inhibitor of aldose reductase in the polyol pathway and is used for the management of diabetic neuropathy clinically. Our pilot experiments and accumulated evidences showed that epalrestat inhibited polyol pathway and reduced sorbitol production, and suggested the potential renal protection effects of epalrestat on diabetic nephropathy (DN). To evaluate the protective effect of epalrestat, the db/db mice were used and exposed to epalrestat for 8 weeks, both the physiopathological condition and function of kidney were examined. For the first time, we showed that epalrestat markedly reduced albuminuria and alleviated the podocyte foot process fusion and interstitial fibrosis of db/db mice. Metabolomics was employed, and metabolites in the plasma, renal cortex, and urine were profiled using a gas chromatography-mass spectrometry (GC/MS)-based metabolomic platform. We observed an elevation of sorbitol and fructose, and a decrease of myo-inositol in the renal cortex of db/db mice. Epalrestat reversed the renal accumulation of the polyol pathway metabolites of sorbitol and fructose, and increased myo-inositol level. Moreover, the upregulation of aldose reductase, fibronectin, collagen III, and TGF-β1 in renal cortex of db/db mice was downregulated by epalrestat. The data suggested that epalrestat has protective effects on DN, and the inhibition of aldose reductase and the modulation of polyol pathway in nephritic cells be a potentially therapeutic strategy for DN.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Gao

Yang

et al. 2018

Acta Pharmacol Sin

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“…15,16 In addition, sterol response elements have been localized within its promoter. 17 The OsRE, ChRE, and OxRE modulate MIOX expression in diabetic states and under high glucose ambience. 14e18 The sterol response elements modulate expression of MIOX in states of obesity, metabolic syndrome, and insulin resistance.…”

mentioning

confidence: 99%

“…14e18 The sterol response elements modulate expression of MIOX in states of obesity, metabolic syndrome, and insulin resistance. 17,18 In addition, posttranslational modifications, such as, serine and threonine phosphorylation, also modulate its enzymatic activity in states of diabetes and obesity. 16,18 Interestingly, MIOX also modulates mitochondrial dynamics in diabetic states.…”

mentioning

confidence: 99%

High Glucose–Induced Hypomethylation Promotes Binding of Sp-1 to Myo-Inositol Oxygenase

Sharma

Dutta

Singh

et al. 2017

The American Journal of Pathology

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The catabolic enzyme myo-inositol oxygenase (MIOX) is expressed in proximal tubules and up-regulated in the diabetic state. Previously, we reported its transcriptional and translation regulation by high glucose (HG), osmolytes, and fatty acids. However, its epigenetic regulation is unknown. Bisulfite sequencing revealed that both human and mouse MIOX promoters, enriched with CpG sites, are hypomethylated and unmethylated under HG ambience and hyperglycemic states associated with increased MIOX expression. Eletrophoretic mobility shift assays revealed increased binding of unmethylated oligos with nucleoproteins of cells maintained under HG. In addition, a strong binding of specificity protein (Sp)-1 transcription factor with MIOX promoter was observed under HG, especially with unmethylated Sp-1 oligo. Specificity of binding was established by supershift assays and treatment with the Sp-1 inhibitor mithramycin. Promoter analysis revealed an increase in luciferase activity under HG, which was reduced after mutation of the Sp-1-binding site. Sp1 siRNA treatment reduced mRNA and protein expression of Sp-1 and MIOX and generation of reactive oxygen species derived from NADPH oxidase (NOX)-4 and mitochondrial sources. In addition, there was reduced expression of hypoxia-inducible factor-1α relevant in the pathogenesis of diabetic nephropathy. Sp1 siRNA treatment reduced fibronectin expression, an extracellular matrix protein that is increased in diabetic nephropathy and tubulopathy. HG-induced MIOX expression was also reduced with the treatment of apelin-13, which deacetylates histones. Overall, these findings highlight the epigenetic regulation of MIOX in the pathogenesis of diabetic tubulopathy.

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“…Depletion of intracellular myo-inositol is a well-known mechanism that counteracts cell swelling [43,44]. Reduction of myo-inositol levels in the kidney may result from its reduced uptake by transporting proteins such as SLC5A3 [45]. It may thus be hypothesized that microRNA-induced changes in expression of NFAT5 and the resulting reduced expression of myo-inositol transporter may represent a mechanism which protects RCC cells against cell swelling-induced death.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-Mediated Metabolic Reprograming in Renal Cancer

Bogusławska

Popławski

Alseekh

et al. 2019

Cancers

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Metabolic reprogramming is one of the hallmarks of renal cell cancer (RCC). We hypothesized that altered metabolism of RCC cells results from dysregulation of microRNAs targeting metabolically relevant genes. Combined large-scale transcriptomic and metabolic analysis of RCC patients tissue samples revealed a group of microRNAs that contribute to metabolic reprogramming in RCC. miRNAs expressions correlated with their predicted target genes and with gas chromatography-mass spectrometry (GC-MS) metabolome profiles of RCC tumors. Assays performed in RCC-derived cell lines showed that miR-146a-5p and miR-155-5p targeted genes of PPP (the pentose phosphate pathway) (G6PD and TKT), the TCA (tricarboxylic acid cycle) cycle (SUCLG2), and arginine metabolism (GATM), respectively. miR-106b-5p and miR-122-5p regulated the NFAT5 osmoregulatory transcription factor. Altered expressions of G6PD, TKT, SUCLG2, GATM, miR-106b-5p, miR-155-5p, and miR-342-3p correlated with poor survival of RCC patients. miR-106b-5p, miR-146a-5p, and miR-342-3p stimulated proliferation of RCC cells. The analysis involving >6000 patients revealed that miR-34a-5p, miR-106b-5p, miR-146a-5p, and miR-155-5p are PanCancer metabomiRs possibly involved in global regulation of cancer metabolism. In conclusion, we found that microRNAs upregulated in renal cancer contribute to disturbed expression of key genes involved in the regulation of RCC metabolome. miR-146a-5p and miR-155-5p emerge as a key “metabomiRs” that target genes of crucial metabolic pathways (PPP (the pentose phosphate pathway), TCA cycle, and arginine metabolism).

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Renal depletion ofmyo-inositol is associated with its increased degradation in animal models of metabolic disease

Cited by 31 publications

References 38 publications

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

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

High Glucose–Induced Hypomethylation Promotes Binding of Sp-1 to Myo-Inositol Oxygenase

MicroRNA-Mediated Metabolic Reprograming in Renal Cancer

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