Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.9.3.1 (cytochrome oxidase)
 8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of novel genes that are up-regulated in diabetic kidneys have been identified. Recently, transforming growth factor-beta (TGF-beta)--driven secreted proteins, i.e., connective tissue growth factor (CTGF) and gremlin, were identified. They are up-regulated in kidneys of diabetic animals and modulate the biology of mesangial cells. CTGF mediates TGF-beta--induced matrix overproduction by the mesangial cells. Gremlin is a putative antagonist of bone morphogenetic protein-2 that blocks mesangial cell proliferation. Thus, gremlin may modulate the biology of mesangium by stimulating mesangial cell proliferation and in turn production of matrix. In addition, transcriptionally regulated kinases, serum glucocorticoid-regulated kinase and munc-13 have been identified. The former stimulates renal tubular Na+ transport and is involved in hyperfiltraion of diabetic kidneys by a Na+ transport feedback mechanism. Munc-13 has been shown to induce apoptosis in hyperglycemic state via diacylglycerol-activated, PKC-independent signaling pathway. Another pathway relevant to diabetic nephropathy is polyol pathway, where glucose is reduced to sorbitol by aldose reductase. Recently, a renal-specific reductase of the aldo-keto reductase family was isolated. It is up-regulated in diabetic mice, and this could serve as a suitable target for gene therapy in renal complications of diabetes. Several mitochondrial genome-encoded genes, such as, cytochrome oxidase and NADH dehydrogenase, are up-regulated in diabetic kidneys. A novel nuclear-encoded mitochondrial gene, i.e., translocase inner mitochondrial membrane 44 (Tim44), is up-regulated in diabetic kidneys, and it may also serve as another target for molecular therapeutic intervention at the core storage energy sites, i.e., mitochondria. In this review, these novel differentially regulated genes that respond to hyperglycemic stress are described, and they may serve as possible targets for gene therapy in the treatment of diabetic nephropathy.
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PMID:Gene expression and identification of gene therapy targets in diabetic nephropathy. 1184 17

Myocardial remodeling and dysfunction are serious complications of type 2 diabetes mellitus (T2DM). Factors controlling their development are not well established. To specifically address the role of the mitochondrial genome, we developed novel conplastic rat strains, i.e. strains with the same nuclear genome but a different mitochondrial genome. The new animals were named T2DN(mtFHH) and T2DN(mtWistar), where the acronym T2DN denotes their common nuclear genome (type 2 diabetic nephropathy (T2DN) rats) and mtFHH or mtWistar the origin of their mitochondria, Fawn Hooded Hypertensive (FHH) or Wistar rats, respectively. The T2DN(mtFHH) and T2DN(mtWistar) showed a similar progression of diabetes as determined by HbA1c, cholesterol, and triglycerides with normal blood pressure, thus enabling investigation of the specific role of the mitochondrial genome in cardiac function without the confounding effects of obesity or hypertension found in other models of diabetes. Echocardiographic analysis of 12-week-old animals showed no abnormalities, but at 12 months of age the T2DN(mtFHH) showed left ventricular remodeling that was verified by histology. Decreased complex I and complex IV but not complex II activity within the electron transport chain was found only in T2DN(mtFHH), which was not explained by differences in protein content. Decreased cardiac ATP levels in T2DN(mtFHH) were in agreement with a lower ATP synthetic capacity by isolated mitochondria. Together, our data provide experimental evidence that mtDNA sequence variations have an additional role in energetic heart deficiency. The mitochondrial DNA background may explain the increased susceptibility of certain T2DM patients to develop myocardial dysfunction.
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PMID:Mitochondrial DNA variant for complex I reveals a role in diabetic cardiac remodeling. 2254 50

Reactive oxygen species (ROS)-mediated disruption of mitochondrial respiratory function has been implicated in the complications of diabetes. The present study examined changes in the gene expression of mitochondrial DNA (mtDNA)-encoded subunits of electron transport chain complexes in response to high glucose-induced ROS overproduction in an in vitro model of diabetic nephropathy using human renal mesangial cells. Mitochondrial ROS generation was assessed by confocal microscopy and flow cytometry in the cells following culture in 5 and 25 mM glucose. The mRNA expression levels of nicotinamide adenine dinucleotide dehydrogenase 2 (ND2) of complex I, cytochrome b (CYTB) of complex III, cytochrome c oxidase (COI) of complex IV and ATPase 6 of complex V were analyzed by reverse transcription-quantitative polymerase chain reaction. The protein expression levels of ND2, CYTB, COI and ATPase 6 were analyzed by western blotting. A significant increase in mitochondrial ROS production was observed in the cells cultured in 25 mM glucose, compared with cells cultured in 5 mM glucose (P<0.05). The mRNA expression of ND2, CYTB, CO1 and ATPase 6 was significantly increased following culture in 25 mM glucose, compared with the cells cultured in 5 mM glucose (P<0.05). This increase in mRNA expression was accompanied by significant increases in protein expression following incubation in 25 mM glucose (P<0.05). The increase in mtDNA-encoded gene expression in the electron transport subunits following exposure to high glucose-induced ROS may be a compensatory response mechanism for the decline in mitochondrial function, which may be important in the development of diabetic nephropathy through enhanced ROS generation.
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PMID:Increased expression of mitochondrial DNA-encoded genes in human renal mesangial cells in response to high glucose-induced reactive oxygen species. 2671 45