UMLS:C0011881 - FACTA Search

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Query: UMLS:C0011881 (diabetic nephropathy)
10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperglycemia directly contributes to the development of diabetic nephropathy. A high-serum glucose concentration alters intraglomerular hemodynamics and promotes deposition of extracellular matrix in the kidney. Nitric oxide (NO) is a short-lived messenger molecule that participates in the regulation of renal blood flow, GFR, and mesangial matrix accumulation. Therefore, in this study it was tested whether high glucose directly modulates NO synthesis by rat mesangial cells in vitro by measuring the accumulation of nitrite, the stable metabolite of NO, in the incubation media. Raising the external glucose concentration to 33.3 mM for 24 to 72 h reduced nitrite levels in cell supernatants in a time-dependent manner to a nadir of 14 +/- 3% of the amount in normal glucose media (5.6 mM) (P < 0.01). The decline in NO synthesis in high glucose media was paralleled by decreased cyclic guanosine monophosphate generation; however, there was no alteration in rat mesangial cell expression of inducible NO synthase protein. The suppressive effect of high glucose on NO production by mesangial cells was not modified by inhibition of protein kinase C (H-7), the addition of antioxidants (vitamin E or superoxide dismutase), or a pan-specific anti-transforming growth factor-beta antibody. An elevated ambient glucose caused a time-dependent reduction in mesangial cell L-arginine content. Addition of L-arginine (10 to 20 mM) to external media partially reversed the inhibitory effect of high glucose on mesangial cell NO production in a dose-dependent manner. The highest dose of L-arginine (20 mM) increased mesangial cell L-arginine content to comparable levels in normal and high glucose media. These results indicate that high glucose causes depletion of L-arginine in mesangial cells and compromises NO synthesis. Limitation in the metabolic precursor and other, as yet unidentified, factors act to reduce NO production by mesangial cells in the presence of an elevated ambient glucose level, a change that may play a role in the development of diabetic glomerulosclerosis.
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PMID:High glucose inhibits nitric oxide production in cultured rat mesangial cells. 925 54

Levels of 15 guanidino compounds and urea were determined in serum and urine of nondialyzed patients with chronic renal insufficiency subdivided according to etiology and creatinine clearances. No significantly different guanidino compound levels in serum and urine were found for the interstitial nephritis, glomerulonephritis, nephrangiosclerosis, and diabetic nephropathy subgroups. Subdividing the patients according to creatinine clearance yields the following results: (1) Serum guanidinosuccinic acid (GSA) and methylguanidine levels of patients with end-stage renal failure (creatinine clearance < 10 mL/min) are up to 100 and 35 times higher than control levels, while guanidine, creatinine, and symmetrical dimethylarginine (SDMA) are increased about 10 times. Serum levels of asymmetrical dimethylarginine (ADMA) are only doubled in end-stage renal failure. Serum levels of guanidinoacetic acid (GAA) and homoarginine are significantly decreased. (2) Urinary excretion levels of most guanidino compounds decrease with decreasing creatinine clearance except for GSA and methylguanidine. (3) Greater than 90% of patients with creatinine clearance ranging from subnormal to 40 mL/min have serum SDMA levels higher than the upper-normal limit; up to 80% have increased GSA levels. (4) The clearance rates of some of the guanidino compounds could be calculated: with the exception of arginine, they decrease with decreasing creatinine clearance. This study shows specific abnormal guanidino compound levels in serum and urine of nondialyzed patients with chronic renal insufficiency that can be used as complementary diagnostic parameters. The best correlation between serum guanidino compound levels and the degree of renal insufficiency is found for GSA, SDMA, methylguanidine, and guanidine. Urinary excretion levels of ADMA correlate best with decreasing creatinine clearance. Serum levels of GSA and especially SDMA are candidate indicators for the onset of renal failure.
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PMID:Guanidino compounds in serum and urine of nondialyzed patients with chronic renal insufficiency. 928 91

Vascular endothelial growth factor (VEGF) stimulates nitric oxide (NO) production by endothelial cells in vitro and in vivo. However, the impact of VEGF on inducible nitric oxide synthase (iNOS) activity and NO synthesis in cultured mesangial cells is not known. Therefore, we measured nitrite accumulation in cytokine-stimulated, rat mesangial cells (RMC) in response to graded concentrations of VEGF. Addition of VEGF (10-50 ng/ml) did not alter RMC viability or NO production in either normal (5.6 mM) or high (33.3 mM) glucose conditions. Exposure of RMC to VEGF did not modify the effects of L-arginine (20 mM) or L-NAME (1 mM) on nitrite accumulation in normal or high glucose media. The steady state abundance of iNOS mRNA and the cytosolic content of iNOS protein were unaffected by addition of VEGF. Cultured RMC expressed the high-affinity tyrosine kinase VEGF receptors, flt and flk/KDR, and the levels were not modulated by incubation in normal or high glucose media. We conclude that VEGF does not regulate proliferation or NO production in cultured RMC. These findings suggest that disturbances in the normal interaction between VEGF and NO are not involved in the pathogenesis of abnormal mesangial cell structure or function in diabetic nephropathy.
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PMID:Effect of vascular endothelial growth factor on nitric oxide production by cultured rat mesangial cells. 957 Nov 72

Integrins represent a superfamily of cell surface molecules that are important mediators of cell-extracellular matrix interactions. Of the many known integrin subunit combinations, only a few (alpha 1 beta 1, alpha 2 beta 1, alpha 3 beta 1, alpha 6 beta 1, alpha 8 beta 1 and alpha v beta 3) appear to play significant roles in renal development and function. The current understanding of these roles is reviewed. Potential therapeutic benefits from the alteration of integrin function by arginine-glycine-aspartic acid peptides in renal ischemic injury have been suggested. Reduced tubular obstruction is a potential mechanism, however other mechanisms remain to be explored. Finally, recent studies suggest a mechanism whereby abnormal interactions between integrins and non-specifically glycosylated glomerular basement membrane components could be involved in the pathogenesis of diabetic nephropathy. The elucidation of other potential pathophysiological roles for integrins in renal disease has just begun.
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PMID:Integrins and the kidney: biology and pathobiology. 991 55

Endothelial dysfunction has been implicated in the pathogenesis of diabetic microangiopathies such as retinopathy and nephropathy as well as macrovascular diseases. The aim of the current study was to determine whether endothelial function in the retinal and renal arteries is impaired in type 2 diabetes mellitus. We examined the effects of an intravenous infusion of L-arginine and a sublingual administration of nitroglycerin on the brachial, retinal, and interlobar arterial hemodynamics in 20 type 2 diabetic patients (10 with normoalbuminuria and 10 with microalbuminuria) and 10 aged-matched control subjects. Despite no difference in the nitroglycerin-induced vascular response of the brachial or retinal artery among the 3 groups, the L-arginine-induced vascular response of each artery was significantly lower in both the normoalbuminuric and microalbuminuric patients than in the control subjects and the microalbuminuric patients showed the lowest value among the 3 groups (P<0.01, each artery, respectively). The L-arginine-induced vascular response of each artery was significantly correlated with HbA1c levels (brachial artery, r=0.617, P=0.0003; retinal artery, r=0.599, P=0.0005; interlobar artery, r=0.636, P=0.0002). In addition, stepwise multiple regression analysis of all subjects showed that HbA1c level was an independent determinant for the L-arginine-induced vascular response of each artery. The results showed that the endothelium-dependent vascular responses of the retinal and intrarenal arteries as well as the brachial artery were impaired in diabetic patients before the clinical manifestation of diabetic nephropathy, and suggest that endothelial dysfunction in these arteries is associated with hyperglycemia in these patients.
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PMID:Impaired endothelium-dependent vascular responses of retinal and intrarenal arteries in patients with type 2 diabetes. 1052 81

This study tested the hypothesis that nitric oxide (NO)-mediated renal vasodilation due to the activity of the inducible nitric oxide synthase (iNOS) contributes to glomerular hyperfiltration in diabetic rats. Two weeks after induction of diabetes mellitus by streptozotocin, mean arterial BP (MAP), GFR (inulin clearance), and renal plasma flow (RPF) (para-aminohippurate clearance) were measured in conscious instrumented rats. Diabetic rats had elevated GFR (3129 +/- 309 microl/min versus 2297 +/- 264 microl/min in untreated control rats, P < 0.05) and RPF (10526 +/- 679 microl/min versus 8005 +/- 534 microl/min), which was prevented by chronic insulin treatment. Intravenous administration of 0.1 and 1 mg of L-imino-ethyl-lysine (L-NIL), an inhibitor of iNOS, did not affect MAP, GFR, or RPF, either in diabetic or control rats. A higher L-NIL dose (10 mg) increased MAP and decreased RPF in diabetic rats significantly (n = 6, P < 0.05), but not in controls (n = 6). In addition, 0.1 mg of NG-nitro-L-arginine methyl ester (L-NAME), a nonselective blocker of NOS isoforms, decreased GFR (2389 +/- 478 microl/min) and RPF (7691 +/- 402 microl/min) in diabetic animals to control levels, while renal hemodynamics in normoglycemic rats were not altered. Higher L-NAME doses (1 and 10 mg) reduced GFR and RPF in diabetic and control rats to identical levels. In glomeruli isolated from diabetic and control rats, neither iNOS mRNA nor iNOS protein expression was detected. In contrast, increased protein levels of endothelial constitutive NOS (ecNOS) were found in glomeruli of diabetic rats compared with controls. By immunohistochemistry, ecNOS but not iNOS staining was observed in the endothelium of preglomerular vessels and in diabetic glomeruli. These results support the notion that increased NO availability due to greater abundance of ecNOS contributes to the pathogenesis of glomerular hyperfiltration in early experimental diabetic nephropathy. In contrast, we found no functional or molecular evidence for increased glomerular expression and activity of iNOS in diabetic rats.
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PMID:Nitric oxide synthase isoforms and glomerular hyperfiltration in early diabetic nephropathy. 1061 42

Glomerular hypertension and hyperglycemia are major determinants of diabetic nephropathy. We sought to identify the mechanisms whereby stretch-induced activation of mesangial cell extracellular signal-regulated kinase 1 and 2 (ERK1/ERK2) is enhanced in high glucose (HG). Mesangial cells cultured on fibronectin Flex I plates in normal glucose (NG; 5.6 mM) or HG (30 mM), were stretched by 15% elongation at 60 cycles/min for up to 60 min. In HG, a 5-min stretch increased ERK1/ERK2 phosphorylation by 6.4 +/- 0.4/4.3 +/- 0.3-fold (P < 0.05 vs. NG stretch). In contrast, p38 phosphorylation was increased identically by stretch in NG and HG. Unlike many effects of HG, augmentation of ERK activity by HG was not dependent on protein kinase C (PKC) as indicated by downregulation of PKC with 24-h phorbol ester or inhibition with bisindolylmaleimide IV. In both NG and HG, pretreatment with arginine-glycine-aspartic acid peptide (0.5 mg/ml) to inhibit integrin binding or with cytochalasin D (100 ng/ml) to disassemble filamentous (F) actin, significantly reduced phosphorylation of ERK1/ERK2 and p38. To determine whether the rate of mitogen-activated protein kinase dephosphorylation is affected by HG, cellular kinase activity was inhibited by depleting ATP. Post-ATP depletion, phosphorylation of ERK1/ERK2 was reduced to 36 +/- 9/51 +/- 14% vs. 9 +/- 5/7 +/- 6% in NG (P < 0.05, n = 5). Thus stretch-induced ERK1/ERK2 and p38 activation in both NG and HG is beta(1)-integrin and F-actin dependent. Stretch-induced ERK1/ERK2 is enhanced in high glucose by diminished dephosphorylation, suggesting reduced phosphatase activity in the diabetic milieu. Enhanced mesangial cell ERK1/ERK2 signaling in response to the combined effects of mechanical stretch and HG may contribute to the pathogenesis of diabetic nephropathy.
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PMID:Stretch-induced mesangial cell ERK1/ERK2 activation is enhanced in high glucose by decreased dephosphorylation. 1099 19

Alterations of intrarenal nitric oxide (NO) synthesis play an important role in the pathogenesis and progression of diabetic nephropathy. We tested the hypothesis that hyperglycemia modulates intrarenal NO synthesis, which might mediate the mesangial cell proliferation and matrix production. Murine mesangial cells were grown in media containing varying glucose concentrations, and cytokine-induced NO synthesis was assayed by chemiluminescence using an NO analyzer. High media glucose (25 mM) inhibited NO synthesis in a time-dependent fashion. This inhibition was posttranslational as revealed by analysis of inducible nitric oxide synthase (iNOS) gene and protein expression. L-Arginine supplementation partially reversed the inhibition whereas addition of tetrahydrobiopterin (BH4), a cofactor for NOS, restored the inducibility of NO synthesis. The in vitro [3H]citrulline assay for iNOS activity indicated that high glucose decreased BH4 availability whereas examination of the BH4 synthetic pathway suggested decreased BH4 stability rather than synthesis, a defect that was corrected by ascorbic acid. We conclude that hyperglycemia inhibits NO synthesis in mesangial cells by a posttranslational defect that might involve the stability and hence availability of BH4.
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PMID:Tetrahydrobiopterin reverses the inhibition of nitric oxide by high glucose in cultured murine mesangial cells. 1139 59

Serum- and glucocorticoid-induced protein kinase 1 (SGK1) was identified in 1993 as an immediate early gene whose mRNA levels increase dramatically within 30 minutes when cells are exposed to serum or glucocorticoids, or both. Subsequently, many other agonists, acting through a variety of signal transduction pathways, have been shown to induce SGK1 gene transcription in cells and tissues. SGK1 is a member of the "AGC" subfamily, which includes protein kinases A, G, and C, and its catalytic domain is most similar to protein kinase B (PKB). Like PKB, SGK1 is activated by phosphorylation in response to signals that stimulate phosphatidylinositol 3-kinase, and this is mediated by 3-phosphoinositide-dependent protein kinase 1 (PDK1) and another protein kinase that has yet to be identified. Thus, SGK1 is remarkable in being activated at both the transcriptional and posttranslational levels by a huge number of extracellular signals. In contrast, little is known about the transcriptional regulation of the two closely related isoforms SGK2 and SGK3, although they can be activated by phosphorylation. The substrate specificity of SGK isoforms superficially resembles that of PKB in that serine and threonine residues lying in Arg-Xaa-Arg-Xaa-Xaa-Ser/Thr sequences (where Xaa is a variable amino acid) are phosphorylated. However, although they may have some substrates in common, evidence is emerging that SGK1 and PKB phosphorylate distinct proteins and have different functions in vivo. In particular, SGK1 plays an important role in activating certain potassium, sodium, and chloride channels, suggesting an involvement in the regulation of processes such as cell survival, neuronal excitability, and renal sodium excretion. Moreover, sustained high levels of SGK1 protein and activity may contribute to conditions such as hypertension and diabetic nephropathy. This raises the possibility that specific inhibitors of SGK1 may have therapeutic potential for the treatment of several diseases.
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PMID:Regulation and physiological roles of serum- and glucocorticoid-induced protein kinase isoforms. 1170 20

The molecular mechanism(s) by which high glucose induces fibronectin expression via G-protein activation in the kidney are largely unknown. This investigation describes the effect of high glucose (HG) on a small GTP-binding protein, Rap1b, expression and activation, and the relevance of protein kinase C (PKC) and Raf pathways in fibronectin synthesis in cultured renal glomerular mesangial cells (MCs). In vivo experiments revealed a dose-dependent increase in Rap1b expression in glomeruli of diabetic rat kidneys. Similarly, in vitro exposure of MCs to HG led to an up-regulation of Rap1b with concomitant increase in fibronectin (FN) mRNA and protein expression. The up-regulation of Rap1b mRNA was mitigated by the PKC inhibitors, calphostin C, and bisindolymaleimide, while also reducing HG- induced FN expression in non-transfected MCs. Overexpression of Rap1b by transfection with pcDNA 3.1/Rap1b in MCs resulted in the stimulation of FN synthesis; however, the PKC inhibitors had no significant effect in reducing FN expression in Rap1b-transfected MCs. Transfection of Rap1b mutants S17N (Ser --> Asn) or T61R (Thr --> Arg) in MCs inhibited the HG-induced increased FN synthesis. B-Raf and Raf-1 expression was investigated to assess whether Rap1b effects are mediated via the Raf pathway. B-Raf, and not Raf-1, expression was increased in MCs transfected with Rap1b. HG also caused activation of Rap1b, which was largely unaffected by anti-platelet-derived growth factor (PDGF) antibodies. HG-induced activation of Rap1b was specific, since Rap2b activation and expression of Rap2a and Rap2b were unaffected by HG. These findings indicate that hyperglycemia and HG cause an activation and up-regulation of Rap1b in renal glomeruli and in cultured MCs, which then stimulates FN synthesis. This effect appears to be PKC-dependent and PDGF-independent, but involves B-Raf, suggesting a novel PKC-Rap1b-B-Raf pathway responsible for HG-induced increased mesangial matrix synthesis, a hallmark of diabetic nephropathy.
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PMID:High glucose stimulates synthesis of fibronectin via a novel protein kinase C, Rap1b, and B-Raf signaling pathway. 3125 89

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