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PubMed1997

Mapping of the gene encoding the B56 beta subunit of protein phosphatase 2A (PPP2R5B) to a 0.5-Mb region of chromosome 11q13 and its exclusion as a candidate gene for multiple endocrine neoplasia type 1 (MEN1).

The multiple endocrine neoplasia type 1 (MEN1) locus has been previously localised to 11q13 by combined tumour deletion mapping and recombination studies, and a 0.5-Mb region, flanked by PYGM and D11S449, has been defined. In the course of constructing a conting, we have identified the location of the gene encoding the B56 beta subunit of protein phosphatase 2A (PP2A), which is involved in cell signal transduction pathways and thus represents a candidate gene for MEN1. We have searched for mutations in the PP2A-B56 beta coding region, together with the 5' and 3' untranslated regions in six MEN1 patients. DNA sequence abnormalities were not identified and thus the PP2A-B56 beta gene is excluded as the candidate gene for MEN1. However, our precise localisation of PP2A-B56 beta to this region of 11q13 may help in elucidating the basis for other disease genes mapping to this generich region.

Chromosome Mapping↗

PubMed2005

Novel target genes of the Wnt pathway and statistical insights into Wnt target promoter regulation.

The Wnt pathway controls biological processes via the regulation of target gene expression. The expression of direct Wnt target genes, e.g. cyclin D1 and MYC, is activated by the transcription factor TCF, which binds to specific sequence motifs in the promoter. Indirect target genes are regulated via transcription regulators, which are targets of the Wnt pathway. As an example, MYC regulates the MYC interacting zinc finger protein-1 (MIZ-1), which is able to inhibit the expression of the indirect target p21WAF1. We intended to identify new Wnt target genes and to get a deeper insight into the regulatory mechanisms of Wnt target gene expression. For this we analyzed the differential expression pattern of Wnt-1 activated cells by microarray analysis. We identified 43 sequences including eight expressed sequence tags (ESTs), which showed increased transcript levels, and 104 sequences including 19 ESTs with decreased RNA levels. Northern blot and real-time quantitative PCR analysis of the differential expression levels of 15 genes confirmed the differential expression trends of eight candidate genes. When the Wnt pathway was regulated at the lower level of glycogen synthase kinase-3 beta (GSK-3 beta) or adenomatous polyposis coli (APC), we detected discrepant expression trends. We compared the number of binding sites of transcription factors in the genomic regions of all candidate target genes with the number of sites in control genes. We found that the genomic regions of the down-regulated genes include an increased number of putative MIZ-1 binding sites. Our study introduces several new Wnt target genes and provides indications that the specific gene expression pattern depends on the type of the activation trigger or the level of interference with the Wnt pathway. Furthermore, our data indicate that a high proportion of Wnt target genes are regulated by indirect mechanisms.

Animals↗

PubMed1987

Stimulation-induced changes in the intracellular sodium activity of the crayfish stretch receptor.

Changes in intracellular Na+ activity (aiNa) caused by mechanical stimulation in the slowly adapting stretch receptor of the crayfish were examined using Na+-selective microelectrodes. A series of brief stretches (each giving rise to a brief receptor potential and a single action potential) induced a reversible increase in aiNa which was proportional to the stimulation frequency in the range examined, 0-9.5 Hz. At 9.5 Hz, aiNa increased by 4-5 mM from the resting value of 7-10 mM. Tetrodotoxin (TTX) reduced, but did not abolish the stimulation-dependent increase in aiNa indicating the involvement of a Na+-influx pathway in addition to the potential-dependent, TTX-sensitive sodium channels of the neuronal plasma membrane. A likely candidate for this TTX-resistant pathway are the cationic transducer channels of the dendrites.

Animals↗

PubMed2004

Genetic determinants of bone mass.

PURPOSE OF REVIEW: This review examines recent advances in the analysis of genetic determinants of bone mass. It addresses both human and animal linkage studies as well as genetic manipulations in animals, inbred mouse models, and candidate gene analyses. RECENT FINDINGS: Recent studies have implicated novel regulatory pathways in bone biology including both the neuroendocrine system and metabolic pathways linked to lipid metabolism. Variations in the lipoprotein receptor-related protein 5 (LRP5), part of the Wnt-frizzled pathway, were independently identified by linkage in high and low bone mass families. Subsequently, other high bone mass syndromes have been shown to have mutations in this gene. Neural studies have shown the skeletal regulatory activity of leptin and neuropeptide Y receptors via the hypothalamus. Subsequently, the beta-adrenergic pathway has been implicated, with important changes in bone mass. The lipoxygenase 12/15 pathway, identified through inbred mouse models and through pharmacologic studies with specific inhibitors, has also been shown to have important effects on bone mass. These studies exemplify the value of genetic models both to identify and then confirm pathways by mutational study and pharmacologic interventions. Continuing candidate gene studies often performed with multiple loci complement such discoveries. However, these studies have not focused on the clinical endpoint of fracture and few have included large enough groups to engender confidence in the associations reported, as such studies may require thousands of individuals. Interestingly, results often differ by ethnicity, age, or gender. A small proportion have examined whether relevant genes influence response to treatment. SUMMARY: The combinations of human and animal genetic linkage studies have advanced understanding of the regulation of bone mass. Studies ranging from linkage to pharmacology provide optimism for new targets and treatments for osteoporosis.

Animals↗

PubMed2026

Transposon insertion sequencing of Pseudomonas aeruginosa identifies multiple intersecting pathways essential for extreme colistin resistance.

Colistin is used to treat antibiotic resistant gram-negative infections, including those caused by Pseudomonas aeruginosa (Pa). Using a diverse collection of clinical isolates, we identified BWH047, a colistin-resistant isolate with an extremely high minimum inhibitory concentration (MIC, 1280 µg/mL). To characterize the genes conditionally essential for colistin resistance in BWH047, we employed transposon insertion sequencing and identified 20 gene candidates. In-frame deletion validated 75% of the candidates and identified genes in several new pathways that contribute to colistin resistance in Pa, including algU and wapH. We also identified several candidate genes from previously reported colistin resistance pathways (e.g., arn, pmrAB). We further investigated the impact of a colistin resistance-associated inner membrane DedA-family undecaprenyl phosphate flippase, which we named DpcA (DedA of Pseudomonas necessary for colistin resistance A). Deletion of dpcA in BWH047 restored sensitivity to colistin (MIC = 0.5 µg/mL) and resulted in several unique changes to the structure of lipopolysaccharide (LPS), including production of decreased amounts of the colistin resistance-conferring 4-amino-4-deoxy-L-arabinose (L-Ara4N) modification on lipid A. This work represents a robust analysis of colistin resistance in Pa and identifies intersecting pathways that contribute to extreme phenotypic resistance.

Pseudomonas aeruginosa↗

PubMed2004

Human carbonyl reduction pathways and a strategy for their study in vitro.

Carbonyl reduction plays a significant role in physiological processes throughout the body. Although much is known about endogenous carbonyl metabolism, much less is known about the roles of carbonyl-reducing enzymes in xenobiotic metabolism. Multiple pathways exist in humans for metabolizing carbonyl moieties of xenobiotics to their corresponding alcohols, readying these molecules for subsequent conjugation and/or excretion. When exploring carbonyl reduction clearance pathways for a drug development candidate, it is possible to assess the relative contributions of these enzymes due to their differences in subcellular locations, cofactor dependence, and inhibitor profiles. In addition, the contributions of these enzymes may be explored by varying incubation conditions, such as pH. Presently, individual isoforms of carbonyl-reducing enzymes are not widely available, either in recombinant or purified form. However, it is possible to study carbonyl reduction clearance pathways from simple experiments with commercially available reagents. This article provides an overview of carbonyl-reducing enzymes, including some kinetic data for substrates and inhibitors. In addition, an experimental strategy for the study of these enzymes in vitro is presented.

Animals↗

PubMed2001

Functional impact of concomitant versus alternative defects in the Chk2-p53 tumour suppressor pathway.

Recent evidence identified a genetic and functional link between Chk2 kinase and p53 as a candidate genome integrity checkpoint and a tumour suppressor pathway. Here we report that in human cells, Chk2 and p53 form protein-protein complexes whose abundance increased upon DNA damage, and whose formation was abrogated through cancer associated mutations in the FHA domain of Chk2, or mutations in the tetramerization domain of p53. Whereas among Li-Fraumeni syndrome families mutations of Chk2 or p53 occur in a mutually exclusive manner, we document that the colon cancer cell line HCT-15 concomitantly lacks functions of both Chk2 and p53, the latter demonstrated by a non-invasive reporter assay monitoring p53-dependent transactivation in live cells. Despite the preserved ability of common cancer-derived mutant p53 proteins to bind and potentially 'titrate' activated Chk2, the integrity of the S phase checkpoint response to ionizing radiation remained largely intact and dependent on Chk2 in cells with wild-type, mutant, or no p53. These results provide new mechanistic insights into the Chk2-p53 interplay, suggest how mutations in Chk2 may abrogate its tumour suppressor function, and indicate that compared with individual defects in either Chk2 or p53, concomitant mutations in both of these cell cycle checkpoint regulators may provide some additional selective advantage to tumour cells.

Checkpoint Kinase 2↗

PubMed2003

Identification and characterization of phenylpyruvate decarboxylase genes in Saccharomyces cerevisiae.

Catabolism of amino acids via the Ehrlich pathway involves transamination to the corresponding alpha-keto acids, followed by decarboxylation to an aldehyde and then reduction to an alcohol. Alternatively, the aldehyde may be oxidized to an acid. This pathway is functional in Saccharomyces cerevisiae, since during growth in glucose-limited chemostat cultures with phenylalanine as the sole nitrogen source, phenylethanol and phenylacetate were produced in quantities that accounted for all of the phenylalanine consumed. Our objective was to identify the structural gene(s) required for the decarboxylation of phenylpyruvate to phenylacetaldehyde, the first specific step in the Ehrlich pathway. S. cerevisiae possesses five candidate genes with sequence similarity to genes encoding thiamine diphosphate-dependent decarboxylases that could encode this activity: YDR380w/ARO10, YDL080C/THI3, PDC1, PDC5, and PDC6. Phenylpyruvate decarboxylase activity was present in cultures grown with phenylalanine as the sole nitrogen source but was absent from ammonia-grown cultures. Furthermore, the transcript level of one candidate gene (ARO10) increased 30-fold when phenylalanine replaced ammonia as the sole nitrogen source. Analyses of phenylalanine catabolite production and phenylpyruvate decarboxylase enzyme assays indicated that ARO10 was sufficient to encode phenylpyruvate decarboxylase activity in the absence of the four other candidate genes. There was also an alternative activity with a higher capacity but lower affinity for phenylpyruvate. The candidate gene THI3 did not itself encode an active phenylpyruvate decarboxylase but was required along with one or more pyruvate decarboxylase genes (PDC1, PDC5, and PDC6) for the alternative activity. The K(m) and V(max) values of the two activities differed, showing that Aro10p is the physiologically relevant phenylpyruvate decarboxylase in wild-type cells. Modifications to this gene could therefore be important for metabolic engineering of the Ehrlich pathway.

Carboxy-Lyases↗

PubMed2004

Investigation of serotonin-related genes in antidepressant response.

In this study, we sought out to test the hypothesis that genetic factors may influence antidepressant response to fluoxetine. The investigation focused on seven candidate genes in the serotonergic pathway involved in the synthesis, transport, recognition, and degradation of serotonin. Our clinical sample consisted of 96 subjects with unipolar major depression treated with fluoxetine with response variables assessed after a 12-week trial. Patient data were also collected to investigate the pattern of drug response. Using a high-throughput single-nucleotide polymorphism (SNP) genotyping platform and capillary electrophoresis, we genotyped patients at 110 SNPs and four repeat polymorphisms located in seven candidate genes (HTR1A, HTR2A, HTR2C, MAOA, SLC6A4, TPH1, and TPH2). Statistical tests performed included single-locus and haplotype association tests, and linkage disequilibrium (LD) estimation. Little evidence of population stratification was observed in the sample with 20 random SNPs using a genomic control procedure. Our most intriguing result involved three SNPs in the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus association when response to fluoxetine is compared to nonresponse (P=0.02-0.04). All odds ratios indicated an increased risk of not responding to fluoxetine. In the specific response vs nonspecific and nonresponse comparison, three SNPs in the TPH2 gene (P=0.02-0.04) were positively associated and one SNP in the HTR2A gene (P=0.02) was negatively associated. When comparing specific response to nonspecific response, we found significant negative associations in three SNPs in the HTR2A gene (P=0.001-0.03) and two SNPs in the MAOA gene (P=0.03-0.05). We observed variable, although strong LD, in each gene and unexpectedly low numbers of estimated haplotypes, formed from tagged SNPs. Significant haplotype associations were found in all but the HTR1A and HTR2C genes. Although these data should be interpreted cautiously due to the small sample size, these results implicate TPH1 and SLC6A4 in general response, and HTR2A, TPH2, and MAOA in the specificity of response to fluoxetine. Intriguingly, we observe that a number of the less frequent alleles of many of the SNP markers were associated with the nonresponse and nonspecific phenotypes.

Antidepressive Agents, Second-Generation↗

PubMed2004

Aging, anti-aging, and hormesis.

As a result of almost 50 years of efforts in collecting descriptive data, biogerontologists are now able to construct general principles of aging and to explore possibilities of gerontomodulation. Most of the data indicate that aging is characterized by a stochastic accumulation of molecular damage and a progressive failure of maintenance and repair, and the genes involved in homeodynamic pathways are the most likely candidate virtual gerontogenes. Several approaches are being tried and tested to modulate aging in a wide variety of organisms, but with the ultimate aim of improving the quality of human life in old age. These approaches include gene therapy, hormonal supplementation, nutritional modulation, and intervention by antioxidants and other molecules. A recent approach is that of applying hormesis in aging research and therapy, which is based on the principle of stimulation of maintenance and repair pathways by repeated exposure to mild stress.

Aging↗

PubMed2000

Glycosylation and protein transport.

Transport along the secretory pathway is largely signal-mediated. Proteins in the secretory pathway can be covalently modified with various carbohydrate structures, most commonly O-glycans, N-glycans and/or proteoglycans. Carbohydrate modifications can change the physical properties of proteins or can function as specific recognition epitopes. Glycosylation can act as an apical sorting signal in polarized epithelial cells and provide a signal for surface transport in non-polarized fibroblasts. Homologues of leguminous plant lectins have been identified in yeast, fruitflies, worms and humans. Intracellular lectins are candidate receptors in the secretory pathway to mediate concentration of cargo in carrier vesicles.

Animals↗

PubMed2026

Integrated Metabolomic and Transcriptomic Analysis Reveals Tissue-Specific Secondary Metabolic Differentiation and Indole Alkaloid Accumulation in Evodia rutaecarpa.

Evodia rutaecarpa is a valuable medicinal plant, yet its non-medicinal tissues remain largely underexplored. Here, we integrated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based widely targeted metabolomics and RNA sequencing (RNA-seq) transcriptomics to systematically profile the metabolic and transcriptional landscapes of roots, stems, leaves, and flowers of Evodia rutaecarpa (Juss.) Benth. Our aim was to characterize tissue-specific metabolic differentiation and its underlying transcriptional regulatory mechanisms. Metabolomic analysis, employing principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) with robust model parameters (R2Y > 0.9, Q2 > 0.5), identified 3090 differential metabolite features (variable importance in projection, VIP > 1.0; p < 0.05) across the four tissues, which exhibited distinct tissue-specific clustering patterns. Integrated Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and weighted gene co-expression network analysis (WGCNA) revealed that roots specifically accumulated quinolone alkaloids and flavonoid glycosides, accompanied by the coordinated upregulation of genes involved in flavonoid and phenylpropanoid biosynthetic pathways. In contrast, stems, leaves, and flowers were enriched in indole alkaloids (evodiamine and rutaecarpine) and volatile oil precursors, with concurrent upregulation of genes involved in tryptophan metabolism and indole alkaloid biosynthesis (e.g., tryptophan decarboxylase, TDC; s N-methyltransferase, NMT). Notably, leaves and flowers displayed particularly high accumulation levels of these bioactive alkaloids, suggesting their potential as alternative sources for industrial and pharmaceutical applications. WGCNA further identified multiple transcription factors and structural gene modules tightly correlated with evodiamine accumulation, offering promising candidate regulators for future biosynthetic pathway engineering. Collectively, this multi-omics integration study systematically elucidates the tissue-partitioned secondary metabolism of Evodia rutaecarpa (Juss.) Benth. and provides a solid scientific foundation for full-plant resource utilization, targeted development of non-medicinal tissues, and future metabolic engineering of indole alkaloid production.

Evodia rutaecarpa↗

PubMed2006

Time-resolved gas-phase kinetic and quantum chemical studies of reactions of silylene with chlorine-containing species. 2. CH3Cl.

Time-resolved kinetic studies of the reaction of silylene, SiH2, generated by laser flash photolysis of both silacyclopent-3-ene and phenylsilane, have been carried out to obtain second-order rate constants for its reaction with CH3Cl. The reaction was studied in the gas phase at six temperatures in the range 294-606 K. The second-order rate constants gave a curved Arrhenius plot with a minimum value at T approximately 370 K. The reaction showed no pressure dependence in the presence of up to 100 Torr SF6. The rate constants, however, showed a weak dependence on laser pulse energy. This suggests an interpretation requiring more than one contributing reaction pathway to SiH2 removal. Apart from a direct reaction of SiH2 with CH3Cl, reaction of SiH2 with CH3 (formed by photodissociation of CH3Cl) seems probable, with contributions of up to 30% to the rates. Ab initio calculations (G3 level) show that the initial step of reaction of SiH2 with CH3Cl is formation of a zwitterionic complex (ylid), but a high-energy barrier rules out the subsequent insertion step. On the other hand, the Cl-abstraction reaction leading to CH3 + ClSiH2 has a low barrier, and therefore, this seems the most likely candidate for the main reaction pathway of SiH2 with CH3Cl. RRKM calculations on the abstraction pathway show that this process alone cannot account for the observed temperature dependence of the rate constants. The data are discussed in light of studies of other silylene reactions with haloalkanes.

Journal Article↗

PubMed2026

Comprehensive Landscape of Post-Translational Modification Alterations in Nephrolithiasis Revealing Activation of Multiple Cell Death Pathways.

Nephrolithiasis is a common urinary disorder characterized by high prevalence and recurrence, but the molecular mechanisms underlying calcium oxalate (CaOx)-crystal-induced renal injury remain incompletely understood. We applied integrated proteomic, phosphoproteomic, acetylomic, and lactylomic analyses to kidney tissues from a mouse model of CaOx nephrolithiasis followed by bioinformatic analysis and experimental validation. We identified 658 differentially expressed proteins, 735 differential phosphorylation sites, 335 differential acetylation sites, and 113 differential lactylation sites. Functional enrichment indicated immune activation, fibrotic remodeling, and alterations in PI3K-Akt, NOD-like receptor, p53, and Toll-like receptor signaling together with changes in fatty acid degradation, the tricarboxylic acid cycle, and glycolysis. Kinase activity prediction suggested the relative activation of multiple cyclin-dependent kinases. Proteins associated with ferroptosis, autophagy, necroptosis, and pyroptosis, including ACSL4, BNIP3, RIPK3, and GSDMD, showed coordinated abundance and modification changes. Several candidate sites, including MTOR_S1849, GCLM_K94, GCLM_S59, and GSS_K172, were also dysregulated. These data provide a multiomics resource for CaOx nephrolithiasis and identify candidate PTM events and regulatory pathways for future mechanistic validation.

Animals↗

PubMed2026

Doublesex gene influences sex differentiation and embryonic development in predatory mite Phytoseiulus persimilis.

BACKGROUND: Phytoseiulus persimilis is an effective biocontrol agent characterized by paternal genome elimination (PGE), an unusual reproductive system in which males eliminate the paternal genome during embryogenesis. However, the molecular mechanism underlying sex determination and reproductive regulation in this species remain poorly understood. RESULTS: Transcriptome-based analyses identified two doublesex (dsx) homologs, Ppdsx1 and Ppdsx2, as candidate regulators of reproduction. Weighted gene co-expression network analysis (WGCNA) assigned Ppdsx2 to a pre-mating-associated co-expression module enriched for reproductive and signaling pathways. Functional analyses revealed clear divergence between the two genes. RNA interference (RNAi) of Ppdsx1 reduced the proportion of female offspring, whereas RNAi of Ppdsx2 induced sex reversal, developmental abnormalities, and impaired egg viability. Yeast two-hybrid and glutathione S-transferase (GST) pull-down assays further demonstrated interactions between Dsx proteins and vitellogenin (Vg)-derived fragments identified from a complementary DNA (cDNA) library screen, suggesting a previously unrecognized connection between sex determination and reproductive nutrient allocation. CONCLUSIONS: Ppdsx1 contributes to maintenance of the female developmental pathway, whereas Ppdsx2 represents a strong candidate component of the PGE-associated sex-determination cascade. The observed Dsx-Vg fragment interaction suggests a potential link between reproductive developmental programs and nutrient allocation pathways. These findings provide new insights into the molecular basis of sex determination and reproductive regulation in phytoseiid mites and establish a foundation for future studies on the coupling of reproductive development and resource allocation. © 2026 Society of Chemical Industry.

Animals↗

PubMed2001

Probing the performance limits of the Escherichia coli metabolic network subject to gene additions or deletions.

An optimization-based procedure for studying the response of metabolic networks after gene knockouts or additions is introduced and applied to a linear flux balance analysis (FBA) Escherichia coli model. Both the gene addition problem of optimally selecting which foreign genes to recombine into E. coli, as well as the gene deletion problem of removing a given number of existing ones, are formulated as mixed-integer optimization problems using binary 0-1 variables. The developed modeling and optimization framework is tested by investigating the effect of gene deletions on biomass production and addressing the maximum theoretical production of the 20 amino acids for aerobic growth on glucose and acetate substrates. In the gene deletion study, the smallest gene set necessary to achieve maximum biomass production in E. coli is determined for aerobic growth on glucose. The subsequent gene knockout analysis indicates that biomass production decreases monotonically, rendering the metabolic network incapable of growth after only 18 gene deletions. In the gene addition study, the E. coli flux balance model is augmented with 3,400 non-E. coli reactions from the KEGG database to form a multispecies model. This model is referred to as the Universal model. This study reveals that the maximum theoretical production of six amino acids could be improved by the addition of only one or two genes to the native amino acid production pathway of E. coli, even though the model could choose from 3,400 foreign reaction candidates. Specifically, manipulation of the arginine production pathway showed the most promise with 8.75% and 9.05% predicted increases with the addition of genes for growth on glucose and acetate, respectively. The mechanism of all suggested enhancements is either by: 1) improving the energy efficiency and/or 2) increasing the carbon conversion efficiency of the production route.

Aerobiosis↗

PubMed2002

Quantitative trait loci analysis of growth response to varying nitrogen sources in Arabidopsis thaliana.

Nitrogen absorption and assimilation is variable among plants as a result of two factors: the source of nitrogen available and the genetic variation among species within the resulting nitrogen pathways. Several genes involved in nitrogen cycling have been identified, yet little is known about the genes that control quantitative responses to different nitrogen sources. With quantitative trait loci (QTL) mapping in Arabidopsis thaliana recombinant inbred lines (Columbia x Landsberg erecta) we have identified chromosomal regions controlling aerial mass, root mass, and root length when plants are grown in nitrate, ammonium, ammonium nitrate, or low nitrogen treatments. A total of 16 QTL ( P < 0.01) were identified among the nitrogen treatments. Most of the QTL were specific to a single treatment. The percentage additive genetic effects of significant QTL were as high as 17%. Five significant QTL corresponded to the locations of candidate genes associated with nitrogen assimilation, while a few QTL corresponded with candidate genes in the developmental pathways. Most QTL were not shared across treatments, suggesting that there is no optimal genotype for all nitrogen sources.

Journal Article↗

PubMed1987

Evidence for existence of polyol pathway in cultured rat mesangial cells.

The accumulation of polyols has been previously found in renal glomeruli isolated from streptozocin-induced diabetic (STZ-D) rats, although the intraglomerular polyol pathway has not been exactly localized. Because we have previously observed mesangial cell dysfunction in STZ-D rats, we examined whether the polyol pathway exists in mesangial cells as a possible candidate of the cause of cellular dysfunction. The activities of two polyol pathway enzymes, aldose reductase and sorbitol dehydrogenase, were clearly detected in the crude homogenate of cultured mesangial cells at higher levels than those of whole glomeruli when DL-glyceraldehyde or D-fructose was used as substrate. When cells were incubated in medium containing 55 mM glucose or galactose, a large amount of sorbitol or galactitol was accumulated intracellularly. The accumulation of polyols was effectively blocked by an aldose reductase inhibitor, ICI 128436. These results suggest that the polyol pathway exists in mesangial cells of rat glomeruli and may play a role in the development of mesangial cell dysfunction found in STZ-D rats.

Aldehyde Reductase↗