UMLS:C0011849 - FACTA Search

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical, experimental, biochemical, and molecular biologic studies all invoke an important role for the renin-angiotensin system (RAS) in the pathogenesis of diabetic complications. Studies of pharmacologic interruption of the RAS with angiotensin-converting enzyme (ACE) inhibition have implicated this hormonal system in the progression of diabetic nephropathy, both experimentally and clinically. Preliminary evidence also suggests a beneficial effect of angiotensin II (Ang II) receptor antagonists. The relative roles of the systemic vs. intrarenal RAS in the pathogenesis of diabetic nephropathy have recently been evaluated. Though plasma renin is generally low, it is not yet clear whether RAS component processing is normal in diabetes; there may be subtle changes in Ang II metabolism which sustain relatively higher plasma Ang II levels. Furthermore, the intrarenal RAS may not be suppressed. Renal renin levels tend to be disproportionately elevated, as compared to plasma renin values. Renal Ang II levels are normal, and renal mRNAs for RAS components have been variable, though not suppressed. In general, lack of RAS suppression (despite plasma volume and increased exchangeable sodium) may indicate inappropriate activity of the RAS in diabetes. Indeed, disproportionate activity of the intrarenal RAS may be a proximate cause of the observed suppression of the systemic RAS. RAS-mediated injury may occur via stimulation of a number of sclerosing mediators, and there is evidence that hyperglycemia acts synergistically with Ang II to promote cellular injury. Together, these recent investigations lend further support to the notion that the RAS plays an important role in diabetic nephropathy, and are beginning to shed light on the mechanisms of progressive renal injury.
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PMID:Physiologic actions and molecular expression of the renin-angiotensin system in the diabetic rat. 993 Mar 80

The mechanisms responsible for the accelerated cardiovascular disease in diabetes, as well as the increased hypertrophic effects of angiotensin II (Ang II) under hyperglycemic conditions, are not very clear. We examined whether the culture of vascular smooth muscle cells (VSMC) under hyperglycemic conditions to simulate the diabetic state can lead to increased activation of key growth- and stress-related kinases, such as the mitogen-activated protein kinases (MAPKs), in the basal state and in response to Ang II. Treatment of porcine VSMC for short time periods (0.5 to 3 hours) with high glucose (HG; 25 mmol/L) markedly increased the activation of the extracellular signal-regulated kinase (ERK1/2) and c-Jun/N-terminal kinase (JNK) relative to cells cultured in normal glucose (NG; 5.5 mmol/L). p38 MAPK also was activated by HG, and this effect remained sustained for several hours. Ang II treatment increased the activity of all 3 families of MAPKs. Ang II-induced ERK activation was potentiated nearly 2-fold in cells treated with HG for 0.5 hour. However, Ang II-induced JNK was not altered. In VSMC cultured for 24 hours with HG, Ang II and HG displayed an additive response on p38 MAPK activity. MAPKs can lead to activation of transcription factors such as activator protein-1 (AP-1). HG alone significantly increased AP-1 DNA-binding activity. Furthermore, Ang II and HG combined had additive effects on AP-1 activity. These results suggest that increased activation of specific MAPKs and downstream transcription factors, such as AP-1, may be key mechanisms for the increased VSMC growth potential of HG alone and of Ang II under HG conditions.
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PMID:Angiotensin II signaling in vascular smooth muscle cells under high glucose conditions. 993 Nov 33

We have previously reported that hyperglycemia in healthy human subjects increased the renal vasodilator response to the angiotensin-converting enzyme inhibitor captopril. This observation raised intriguing possibilities relevant to the pathogenesis of nephropathy in patients with diabetes mellitus. To ascertain whether the effect of captopril was indeed mediated by a reduction in angiotensin II (Ang II) formation, we performed another study in which an Ang II antagonist, eprosartan, was used in place of captopril. Nine healthy subjects were studied in high sodium balance (ie, sodium intake 200 mmol/d). On the first day, the subjects received 600 mg eprosartan orally, and renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured. Glucose was infused intravenously on the second and third study days to increase plasma glucose to a level below the threshold for glycosuria ( approximately 8.8 mmol/L). Eprosartan at a dose of 600 mg or placebo was administered randomly on the second or third study day 1 hour after initiation of glucose infusion. RPF increased (by 76+/-7 mL. min(-1). 1.73 m(-2), P<0.01) in response to sustained moderate hyperglycemia and then increased further (by 147+/-15 mL. min(-1). 1. 73 m(-2), P<0.01) when eprosartan was administered during hyperglycemia. Eprosartan, conversely, did not affect RPF and GFR in normoglycemic subjects. GFR was not affected by either hyperglycemia or eprosartan. Neither plasma renin activity nor plasma Ang II concentration changed during hyperglycemia, suggesting that the hormonal responses responsible for the enhanced renal vasodilator response to eprosartan occurred within the kidney. The enhancement of the renal vasodilator effect of eprosartan during hyperglycemia is consistent with activation of the intrarenal renin-angiotensin system.
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PMID:Effect of angiotensin II antagonist eprosartan on hyperglycemia-induced activation of intrarenal renin-angiotensin system in healthy humans. 1090 23

Diabetes mellitus, a highly prevalent metabolic and vascular disease, affects 155 million people worldwide. Tight blood glucose control can significantly reduce the incidence of diabetic retinopathy, nephropathy, and neuropathy, but does not appear to significantly reduce its macrovascular complications. Several randomized clinical trials indicate that tight blood pressure control can reduce the risk of microvascular and macrovascular complications in patients with diabetes and hypertension. Blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors has proven effective both in lowering blood pressure and in independently slowing the progression of nephropathy. If instituted early, ACE inhibitor therapy potentially may prevent progression to end-stage renal disease in normotensive patients with type 1 or 2 diabetes. Additionally, ACE inhibitors may reduce cardiovascular morbidity and mortality in this patient population. Angiotensin II (Ang II) receptor blockers (ARBs), which attenuate the deleterious effects of the RAS via blockade of the Ang II subtype 1 receptor, may also be beneficial. Clinical trials are under way to evaluate this possibility.
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PMID:Treating high-risk diabetic hypertensive patients with comorbid conditions. 1098 54

The renin-angiotensin system (RAS) regulates blood pressure, volume, and electrolyte balance. Derangements of the RAS may contribute to hypertension and renal injury, particularly in patients with types 1 or 2 diabetes. Angiotensin-converting enzyme (ACE) inhibitors have been proven to be beneficial in patients with hypertension and diabetes by preventing or delaying the development and progression of proteinuria and glomerulosclerosis. Comparisons with other drug classes demonstrate renoprotective effects for ACE inhibitors that are independent of-and additive to-their systemic antihypertensive actions. These renal effects may derive from their preferential dilation of renal efferent arterioles, which further reduces intraglomerular pressure. Inhibition of angiotensin II (Ang II) synthesis is subtotal, however, because local non-ACE enzymes also convert Ang I to Ang II. The existence of alternative pathways for Ang II generation that are unaffected by ACE inhibitors raises questions about whether ACE is the optimal target for RAS suppression. Ang II receptor blockers (ARBs), which interrupt the RAS at the target-organ receptor level, will block the effect of angiotensin whether its production involved ACE or a non-ACE pathway. ARBs are currently undergoing clinical trials to assess their efficacy in hypertensive patients with nephropathy.
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PMID:Impact of angiotensin II on the kidney: does an angiotensin II receptor blocker make sense? 1098 55

Considerable evidence suggests that the intrarenal renin-angiotensin system plays an important role in diabetic nephropathy. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (Ang II) receptor blockers (ARBs) can attenuate progressive glomerulosclerosis in disease models and can slow disease progression in humans. Because agents that interfere with Ang II action may decrease glomerular injury without altering glomerular pressures, it has been suggested that Ang II has direct effects on glomerular cells to induce sclerosis independent of its hemodynamic actions. To study nonhemodynamic effects of Ang II on matrix metabolism, many investigators have used cell culture systems. Glucose and Ang II have been shown to produce similar effects on renal cells in culture. For instance, incubation of mesangial cells in high-glucose media or in the presence of Ang II stimulates matrix protein synthesis and inhibits degradative enzyme (e.g., collagenase, plasmin) activity. Glucose and Ang II also can inhibit proximal tubule proteinases. Glucose increases expression of the angiotensinogen gene in proximal tubule cells and Ang II production in primary mesangial cell culture, which indicates that high glucose itself can activate the renin-angiotensin system. The effects of glucose and Ang II on mesangial matrix metabolism may be mediated by transforming growth factor-beta (TGF-beta). Exposure of mesangial cells to glucose or Ang II increases TGF-beta expression and secretion. Their effects on matrix metabolism can be blocked by anti-TGF-beta antibody or ARBs such as losartan, which also prevents the glucose-induced increment in TGF-beta secretion. Taken together, these findings support the hypothesis that the high-glucose milieu of diabetes increases Ang II production by renal, and especially, mesangial cells, which results in stimulation of TGF-beta secretion, leading to increased synthesis and decreased degradation of matrix proteins, thus producing matrix accumulation. This may be an important mechanism linking hyperglycemia and Ang II in the pathogenesis of diabetic nephropathy.
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PMID:Role of angiotensin II in diabetic nephropathy. 1099 97

Diabetes in its early stages is associated with enhanced glomerular blood flow and systemic vasodilation. Possible consequences of enhanced glomerular blood flow are glomerular hypertrophy, increased shear stress, and subsequent glomerulosclerosis. The prosclerotic cytokine, transforming growth factor-beta (TGF-beta), has been well established to play a key role in mesangial matrix accumulation in diabetes; however, its role in regulating vascular tone has not been studied in depth. Earlier studies have demonstrated that vascular smooth muscle cells and mesangial cells pretreated with TGF-beta have impaired calcium mobilization to inositol 1,4,5-trisphosphate (IP3) generating agonists, such as platelet-derived growth factor (PDGF) and Angiotensin I1 (Ang II). We postulated that this action of TGF-beta may be caused by regulation of the key intracellular calcium channel, the inositol 1,4,5-trisphosphate receptor (IP3R). Mesangial and smooth muscle cells primarily contain the types I IP3R and III IP3R isoforms. Short-term exposure of mesangial cells to TGF-beta (15-60 min) leads to phosphorylation of the type I IP3R at specific serine residues. Long-term exposure of mesangial cells to TGF-beta (24 hours) leads to down-regulation of protein levels of both types I and III IP3Rs as assessed by Western blot and confocal analysis. Permeabilization of cells and exposure to IP3 leads to impaired calcium mobilization if cells are pretreated with TGF-beta. As an in vivo correlation, we found that streptozotocin-induced diabetic rats and mice have reduced renal type I IP3R expression. By immunostaining, we found reduction of type I IP3R in glomerular cells and arteriolar smooth muscle cells of the diabetic rat kidney. Treatment of diabetic mice with a neutralizing anti-TGF-beta antibody completely prevents diabetic glomerular hypertrophy. We conclude that the vascular dysfunction of diabetes leading to glomerular hypertrophy is mediated, in part, by TGF-beta-induced regulation of IP3Rs.
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PMID:Regulation of inositol 1,4,5-trisphosphate receptors by transforming growth factor-beta: implications for vascular dysfunction in diabetes. 1099 98

Pathogenesis of macrovascular complications of diabetes may involve an activation of the transcription factor nuclear factor-kappaB (NF-kappaB) by hyperglycemia and advanced glycosylation end products (AGEs). Activation of NF-kappaB is believed to be dependent on activation of the Rho family of GTPases. Although the precise mechanism of the Rho-mediated action is not completely understood, posttranslational modification of the Rho proteins by geranylgeranylation is required for their subsequent activation. We observed that in cultured vascular smooth muscle cells (VSMCs), insulin stimulated the activity of geranylgeranyltransferase (GGTase) I and increased the amounts of geranylgeranylated Rho-A from 47% to 60% (P:<0.05). GGTI-286, an inhibitor of GGTase I, blocked both effects of insulin. Increased availability of prenylated Rho-A significantly augmented the abilities of angiotensin II (Ang II), hyperglycemia, and AGEs to activate NF-kappaB, as measured by NF-kappaB response-element luciferase reporter activity. Preincubations of VSMCs with insulin for 24 hours doubled NF-kappaB transactivation by Ang II, hyperglycemia, and AGEs. This priming effect of insulin was completely inhibited by GGTI-286. We demonstrate for the first time, to our knowledge, that insulin potentiates NF-kappaB-dependent transcriptional activity induced by hyperglycemia, AGEs, and Ang II in VSMCs by increasing the activity of GGTase I and the availability of geranylgeranylated Rho-A.
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PMID:Hyperinsulinemia enhances transcriptional activity of nuclear factor-kappaB induced by angiotensin II, hyperglycemia, and advanced glycosylation end products in vascular smooth muscle cells. 1105 72

The renin-angiotensin system is upregulated with diabetes, and this may contribute to the development of a dilated myopathy. Angiotensin II (Ang II) locally may lead to oxidative damage, activating cardiac cell death. Moreover, diabetes and hypertension could synergistically impair myocardial structure and function. Therefore, apoptosis and necrosis were measured in ventricular myocardial biopsies obtained from diabetic and diabetic-hypertensive patients. Accumulation of a marker of oxidative stress, nitrotyrosine, and Ang II labeling were evaluated quantitatively. The diabetic heart showed cardiac hypertrophy, cavitary dilation, and depressed ventricular performance. These alterations were more severe with diabetes and hypertension. Diabetes was characterized by an 85-fold, 61-fold, and 26-fold increase in apoptosis of myocytes, endothelial cells, and fibroblasts, respectively. Apoptosis in cardiac cells did not increase additionally with diabetes and hypertension. Diabetes increased necrosis by 4-fold in myocytes, 9-fold in endothelial cells, and 6-fold in fibroblasts. However, diabetes and hypertension increased necrosis by 7-fold in myocytes and 18-fold in endothelial cells. Similarly, Ang II labeling in myocytes and endothelial cells increased more with diabetes and hypertension than with diabetes alone. Nitrotyrosine localization in cardiac cells followed a comparable pattern. In spite of the difference in the number of nitrotyrosine-positive cells with diabetes and with diabetes and hypertension, apoptosis and necrosis of myocytes, endothelial cells, and fibroblasts were detected only in cells containing this modified amino acid. In conclusion, local increases in Ang II with diabetes and with diabetes and hypertension may enhance oxidative damage, activating cardiac cell apoptosis and necrosis.
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PMID:Myocardial cell death in human diabetes. 1111 Jul 69

Studies have shown that high levels of glucose and angiotensin II (Ang II) stimulate hypertrophy and the expression of matrix protein genes in mouse proximal tubular cells in vitro. The present study tested the hypothesis that blockade of the renin-angiotensin system (RAS) inhibits the stimulatory effect of high levels of glucose on the expression of the renal angiotensinogen (ANG) gene and the formation of Ang II and subsequently attenuates the induction of hypertrophy in kidney proximal tubular cells. Immortalized rat proximal tubular cells (IRPTC) were cultured in monolayer. The levels of expression of rat ANG and ANG mRNA in the IRPTC were quantified by specific radioimmunoassays for rat ANG (RIA-rANG) and by a reverse-transcription polymerase chain reaction (RT-PCR) assay, respectively. Hypertrophy of IRPTC was analyzed by flow cytometry (FACScan) and cellular protein assay. Our studies showed that losartan (an Ang II (AT(1))-receptor blocker), perindopril and captopril (inhibitors of angiotensin-converting enzyme) blocked the stimulatory effect of a high level of glucose (i.e. 25 mM) on the expression of the rat ANG gene and hypertrophy in IRPTC but not by the Ang II (AT(2))-receptor blocker. Our studies indicate that the blockade of RAS is effective in inhibiting the stimulatory effect of hyperglycemia on the expression of the ANG gene and hypertrophy in IRPTC, supporting the notion that the local formation of intrarenal Ang II may play a role in the development of renal hypertrophy during early diabetes.
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PMID:Effect of renin-angiotensin system blockade on the expression of the angiotensinogen gene and induction of hypertrophy in rat kidney proximal tubular cells. 1115 Aug 59

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