Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Curcumin, the coloring principle of the commonly used spice turmeric (Curcuma longa) was fed at 0.5% in the diet to streptozotocin-induced diabetic Wistar rats for 8 weeks. Renal damage was assessed by the amount of proteins excreted in the urine and the extent of leaching of renal tubular enzymes: NAG, LDH, AsAT, AlAT, alkaline and acid phosphatases. The integrity of kidney was assessed by measuring the activities of several key enzymes of the renal tissue: glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, and LDH (Carbohydrate metabolism), aldose reductase and sorbitol dehydrogenase (polyol pathway), transaminases, ATPases and membrane PUFA/SFA ratio (membrane integrity). Data on enzymuria, albuminuria, activity of kidney ATPases and fatty acid composition of renal membranes in diabetic condition suggested that dietary curcumin brought about significant beneficial modulation of the progression of renal lesions in diabetes. These findings were also corroborated by histological examination of kidney sections. It is inferred that this beneficial ameliorating influence of dietary curcumin on diabetic nephropathy is possibly mediated through its ability to lower blood cholesterol levels.
Mol Cell Biochem 1998 Apr
PMID:Amelioration of renal lesions associated with diabetes by dietary curcumin in streptozotocin diabetic rats. 956 45

Nitric oxide (NO) contributes to the alterations in glomerular hemodynamics and extracellular matrix accumulation observed in diabetic nephropathy. High glucose concentrations directly inhibit NO production by rat mesangial cells (RMC). However, the role of peptide growth factors and chemokines in regulating NO synthesis by RMC under normal and high glucose conditions has not been studied. Therefore, we examined the effect of IGF-I, EGF, TGF-beta and RANTES on NO production by RMC maintained in normal (5.6 mM) or high glucose (33.3 mM) for 48 h. No synthesis was determined by measuring nitrite accumulation in conditioned media with the Greiss reaction. In normal glucose media, IGF-I, EGF, and RANTES had no effect on nitrite accumulation while TGF-beta inhibited NO synthesis. In high glucose conditions, IGF-I and EGF significantly enhanced NO production. The effects of RANTES and TGF-beta were unchanged by an elevated glucose concentration. EGF-induced stimulation of NO production in high glucose media was associated with parallel alterations in iNOS gene and protein expression. The modest enhancement in nitrite accumulation provoked by IGF-I in high glucose conditions was not accompanied by demonstrable increases in iNOS mRNA abundance or protein content. In conclusion, peptide growth factors modulate the direct inhibitory effect of high glucose on NO production by cultured mesangial cells. These actions in vivo may limit the adverse consequences of reduced NO production in promoting diabetic nephropathy.
Res Commun Mol Pathol Pharmacol 1998 May
PMID:High glucose enhances growth factor-stimulated nitric oxide production by cultured rat mesangial cells. 966 75

Advanced glycation end-products (AGEs) are assumed to play a major role in the genesis of diabetic nephropathy and other diabetic complications. We studied the potential effect of AGEs on protein turnover and lysosomal proteinase activities in LLC-PK1 cells, a pig kidney proximal tubules cell line. Advanced glycated bovine serum albumin (AGE-BSA) was used as a model of AGEs and its action was compared to that of nonglycated BSA. AGE-BSA but not BSA (50 micromol/l) induced a significant increase in cell volume (BSA: 4870.6 +/- 74.8 fl, AGE-BSA: 5718.0 +/- 20.7 fl, p<0.01). Protein degradation rate was decreased by 13.8% after 48 hrs. incubation with AGE-BSA (p<0.01) while protein synthesis increased by 19,1%, (p<0.01). After incubation with AGE-BSA but not BSA activities of lysosomal cathepsins (B, L+B and H) decreased in a time- and dose-dependent fashion. This decline was neither caused by a shift in lysosomal pH outside the optimal range for cathepsins, nor by a direct inhibitory effect of AGEs modified proteins or peptides but most probably by inhibition of cathepsin B expression as measured by RT-PCR. It is supposed that impaired protease activities participated in decreased protein breakdown and cell enlargement. For the first time our data provide the evidence that AGEs induce hypertrophy of LLC-PK1 cells due to decreased protein breakdown resulting from reduced lysosomal proteinase activities with a concomitant stimulation of protein synthesis.
Cell Mol Biol (Noisy-le-grand) 1998 Nov
PMID:Advanced glycated albumin impairs protein degradation in the kidney proximal tubules cell line LLC-PK1. 984 87

A missense mutation in the methylenetetrahydrofolate reductase gene (MTHFR), C677T, results in a thermolabile variant with reduced activity. Elevated levels of homocysteine have been recognized as a risk factor for vascular disease. Insulin-dependent diabetes mellitus (IDDM) is characterized by a higher prevalence of vascular complications. We analyzed the frequency of C677T MTHFR in IDDM and control groups. The genotype distribution did not differ between control subjects (n = 297) and IDDM patients (n = 392) (chi(2) = 5.413, df = 2, P > 0.05). The MTHFR T677T genotype was found significantly more frequently in IDDM patients with diabetic nephropathy (0.216) compared with the IDDM patients without nephropathy (0.056); the odds ratio was 2.635 (95% CI 1.768-3.927). Thus, we suggest that the T677T genotype of the MTHFR gene is an independent risk factor for diabetic nephropathy in IDDM.
Mol Genet Metab 1999 Nov
PMID:Methylenetetrahydrofolate reductase gene polymorphism as a risk factor for diabetic nephropathy in IDDM patients. 1056 65

The ubiquitous form of the sodium-hydrogen exchanger, NHE1, is devoted to the regulation of intracellular pH and cell volume. In addition, NHE1 activity is stimulated by growth factors and increased NHE rates are found in both circulating and immortalized cells during diabetes or diabetic nephropathy. In this context, we searched for polymorphisms of the 5'-flanking regulatory region of NHE1 gene in subjects with type-I diabetes. We identified a C/T transition 696 bases upstream the translation initiation start site which disrupts a repeated palindromic GC sequence. The TT genotype was significantly more frequent in type-1 diabetics and may have functional importance. Genetic linkage between NHE1 and diabetes has been previously described in NOD mice strains with consequences on NHE rates. Hence, the polymorphism described hereby may act as a predisposition factor to type-I diabetes or to diabetic complications, and may be useful to investigate the genetic involvement of NHE1 in human pathophysiology.
Mol Cell Biol Res Commun 2000 Mar
PMID:Polymorphism of the 5' untranslated region of NHE1 gene associated with type-I diabetes. 1086 Aug 61

Polymorphic tetranucleotide microsatellites D3S1512, D3S1744, D3S1550, and D3S232 were used to study the association of chromosome region 3q21-q25 neighboring the angiotensin II receptor type 1 gene (AT2R1) with diabetic nephropathy (DN) in diabetes mellitus type 1 (DM1). Allele and genotype frequencies were compared for DM1 patients with (N = 39) or without (N = 62) DN. Fisher's exact test with Bonferroni's correction revealed significant differences in frequencies of two D3S2326 alleles, one D3S1512 allele, and one allele and one genotype of D3S1550. No significant difference was observed with D3S1744. Thus, region 3q21-q25 proved tightly associated with DN in ethnic Russians with DM1 from Moscow.
Mol Biol (Mosk)
PMID:[Identification of the locus associated with diabetic nephropathy in type 1 diabetes mellitus]. 1250 May 39

Meprins are multidomain zinc metalloproteases that are highly expressed in mammalian kidney and intestinal brush border membranes and in leukocytes and certain cancer cells. Mature meprins are oligomers of evolutionarily related, separately encoded alpha and/or beta subunits. Homooligomers of meprin alpha are secreted; oligomers containing meprin beta are plasma membrane associated. Meprin substrates include bioactive peptides and extracellular matrix proteins. Meprins have been implicated in cancer and intestinal inflammation. Additionally, meprin beta is a candidate gene for diabetic nephropathy. To elucidate in vivo functions of these metalloproteases, meprin beta null mice were generated by targeted disruption of the meprin beta gene on mouse chromosome 18q12. Analyses of meprin beta knockout mice indicated that (i) 50% fewer null mice are born than the Mendelian distribution predicts, (ii) null mice that survive develop normally and are viable and fertile, (iii) meprin beta knockout mice lack membrane-associated meprin alpha in kidney and intestine, and (iv) null mice have changes in renal gene expression profiles compared to wild-type mice as assessed by microarray analyses. Thus, disruption of the meprin beta allele in mice affects embryonic viability, birth weight, renal gene expression profiles, and the distribution of meprin alpha in kidney and intestine.
Mol Cell Biol 2003 Feb
PMID:Targeted disruption of the meprin beta gene in mice leads to underrepresentation of knockout mice and changes in renal gene expression profiles. 1255 82

The objective of this study was to investigate the association between the heparan sulfate proteoglycan (HSPG) gene G/T polymorphism and diabetic nephropathy in type 2 diabetes in Chinese. The HSPG gene polymorphism (G/T) was determined using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) in 290 Chinese type 2 diabetes mellitus patients comprising 77 cases without nephropathy and 213 cases with nephropathy with either proteinuria (163) or renal insufficiency (50) and a control group of 190 non-diabetics. A significant increase in the frequencies of the T allele and TT + TG genotype was observed in subjects with diabetic renal insufficiency as compared with diabetic subjects without nephropathy and those with diabetic proteinuria (for the T allele: Fisher's two-tailed exact p was 0.015 and 0.002, respectively; for the TT + TG genotype; both p values were < 0.001). Diabetic subjects without nephropathy and those with albuminuria carrying the T allele had odds ratios for the development of renal insufficiency of 1.92 (95% CI, 1.12-3.30) and 2.09 (95% CI, 1.29-3.38), respectively, as compared to non-carriers. The T allele of the HSPG gene BamHI polymorphism located in intron 6 may be a risk factor for the development of renal insufficiency in type 2 diabetes mellitus for Chinese.
Mol Cell Biochem 2003 Mar
PMID:The heparan sulfate proteoglycan gene polymorphism: association with type 2 diabetic nephropathy in Chinese. 1270 51

The objective of this paper is to investigate co-inheritance of specific HSPG and ApoE genotypes in the development of Chinese type 2 diabetic nephropathy. PCR-RFLP was used to detect HSPG and ApoE genotypes in 385 Chinese subjects including 298 patients with type 2 diabetes mellitus (T2DM) and 87 non-diabetic controls (Non-DM). The T2DM group was subdivided into patients with (TDN; n = 218) and without diabetic nephropathy (Non-DN; n = 80). The latter group was further subdivided into groups of patients with microalbuminuria nephropathy (DN-1; n = 129) and severe diabetic nephropathy (DN-2; n = 89). We then compared the relative frequencies of various HSPG and ApoE genotypes and alleles among the groups, searching for predictive trends. The T allele of the HSPG gene occurred more frequently in the DN-2 group than in the Non-DN or DN-1 groups, their Fisher's exact p was 1.05 x 10(-3) and 6.58 x 10(-6); odds ratios were 2.09 (95% CI 1.32-3.30) and 2.48 (95% CI 1.64-3.74), respectively. The E2 allele of the ApoE gene occurred more frequently in the T2DM than in the Non-DM group, the Fisher's exact p was 0.0087; odds ratio was 3.45 (95% CI 1.30-9.81). Genotype analysis showed that the TT or TG of HSPG gene were paired with the E2/2 or E2/3 of ApoE gene significantly more frequently in the TDN group than in the Non-DN group, with an odds ratio of 3.03 (95% CI 1.03-8.90). There was no significant differences in other combinations of genotypes in HSPG and ApoE genes between TDN and Non-DN group. These results suggest that the HSPG T allele is a risk factor for the development of severe diabetic nephropathy in type 2 diabetic patients, and that the ApoE E2 allele is a risk factor for the occurrence of type 2 diabetes mellitus in Chinese general population. In addition, we find that co-inheritance of T/E2 confers a higher risk of type 2 diabetes mellitus progression to diabetic nephropathy in Chinese.
Mol Cell Biochem 2003 Dec
PMID:Co-inheritance of specific genotypes of HSPG and ApoE gene increases risk of type 2 diabetic nephropathy. 1467 16

Diabetic nephropathy is related to glomerular extracellular matrix (ECM) accumulation that leads to glomerulosclerosis. Fluvastatin as a lipid-lowering medicine significantly prevents diabetic nephropathy, probably not only through its lipid-lowering action, but also mainly through its direct suppression of glomerular ECM accumulation. To test this hypothesis, in the present study, a five-sixths nephrectomized (5/6Nx) rat model to induce a renal ECM accumulation without coexistence of hyperlipidemia was used to investigate the effect of fluvastatin on renal function, glomerular ECM accumulation and expression of connective tissue growth factor (CTGF). 5/6Nx induced a significant nephropathy in rats at 13 weeks, indicated by renal dysfunction including increases in blood urine nitrogen, creatinine and urinary protein excretion, and renal histopathological changes. Administration of fluvastatin significantly prevented the renal dysfunction and histological abnormalities in the 5/6Nx rats. Furthermore, both significant suppression of matrix metalloproteinases (MMPs) activity such as MMP-2 and significant activation of tissue inhibitors of MMP (TIMPs) such as TIMP-2 observed in the 5/6Nx rats were almost completely prevented by fluvastatin, resulting in a significant prevention of glomerular ECM accumulation. For upstream mediator of ECM accumulation, 5/6Nx significantly up-regulated CTGF mRNA expression, but fluvastatin treatment prevented CTGF up-regulation. These results suggest that fluvastatin, as one of well-known lipid-lowering agents, plays an important role in the prevention of nephropathy, likely through suppression of CTGF-mediated ECM accumulation. Therefore, fluvastatin may be a potential candidate for developing a pharmaceutical approach to the prevention of diabetic nephropathy due to its both lipid-lowering and direct anti-renal ECM accumulation actions.
Exp Mol Pathol 2004 Feb
PMID:Fluvastatin prevents nephropathy likely through suppression of connective tissue growth factor-mediated extracellular matrix accumulation. 1473 71


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