UMLS:C0011849 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

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

In the present study, we investigated the effects of the angiotensin (Ang) II receptor antagonist, irbesartan, on blood pressure and renal structural injury in obese Zucker rats (OZR), an experimental model of non-insulin-dependent diabetes mellitus (NIDDM). Twenty-six-week-old OZR with established renal disease were administered either low-dose (15 mg/kg) or high-dose (50 mg/kg) irbesartan in the drinking water for a period of 18 weeks. Irbesartan caused dose-related reductions in blood pressure, and reduced by 47 to 60% the percent of glomeruli with sclerosis at 44 weeks of age (P < 0.05). In addition, irbesartan at the higher dose reduced the tubulointerstitial injury score at 44 weeks by approximately 75% (P < 0.05). By contrast, irbesartan did not significantly reduce albuminuria in OZR. The results of the present study demonstrate that the Ang II receptor antagonist irbesartan can reduce blood pressure and ameliorate glomerular and tubulointerstitial injury in an experimental model of NIDDM.
...
PMID:Irbesartan lowers blood pressure and ameliorates renal injury in experimental non-insulin-dependent diabetes mellitus. 940 64

Dietary sodium restriction has a variety of effects on metabolism, including activation of the renin-angiotensin system. Angiotensin II has complex metabolic and cardiovascular effects, and these may be relevant to the effects of both nonpharmacological and pharmacological interventions in noninsulin-dependent diabetes mellitus (NIDDM). We have assessed the effect of dietary sodium restriction on insulin sensitivity and endogenous glucose production in eight normotensive patients with diet-controlled NIDDM who underwent hyperinsulinemic clamp studies in a randomized, double-blind, placebo-controlled cross-over protocol after two 4-day periods on sodium replete (160 mmol/day) and sodium deplete (40 mmol/day) diets. Mean +/- SD 24-h urinary sodium was 197 +/- 76.0 mmol (replete) and 67 +/- 19.5 mmol (deplete), P = 0.03. Insulin sensitivity was 42.0 +/- 11.3 mumol/kg.min (replete) and 37.0 +/- 11.6 mumol/kg.min (deplete), P = 0.04 (a reduction of 12%). Blood pressure was 130 +/- 21/78 +/- 11 mmHg (replete) and 128 +/- 12/73 +/- 10 mmHg (deplete). Dietary sodium restriction may result in a decrease in peripheral insulin sensitivity in normotensive patients with NIDDM, possibly via an elevation in prevailing angiotensin II concentrations.
...
PMID:Dietary sodium restriction impairs insulin sensitivity in noninsulin-dependent diabetes mellitus. 958 54

Multiple lines of evidence have suggested that alternative pathways to the angiotensin-converting enzyme (ACE) exists for angiotensin II (Ang II) generation in the heart, large arteries, and the kidney. In vitro studies in intact tissues, homogenates, or membrane isolates from the heart and large arteries have repeatedly demonstrated such pathways, but the issue remains unresolved because the approaches used have not made it possible to extrapolate from the in vitro to the in vivo situation. For our in vivo model, we studied young and healthy human volunteers, for the most part white and male; when these subjects achieved balance on a low salt diet to activate the renin system, the response of renal perfusion to pharmacological interruption of the renin system was studied. With this approach, we studied the renal vasodilator response to 3 ACE inhibitors, 2 renin inhibitors, and 2 Ang II antagonists at the top of their respective dose-response relationships. When these studies were initiated, our premise was that a kinin-dependent mechanism contributed to the renal hemodynamic response to ACE inhibition; therefore, the renal vasodilator response to ACE inhibition would exceed the alternatives. To our surprise, both renin inhibitors and both Ang II antagonists that were studied induced a renal vasodilator response of 140 to 150 mL/min/1.73 m2, approximately 50% larger than the maximal renal hemodynamic response to ACE inhibition, which was 90 to 100 mL/min/1.73 m2. In light of the data from in vitro systems, our findings indicate that in the intact human kidney, virtually all Ang II generation is renin-dependent but at least 40% of Ang I is converted to Ang II by pathways other than ACE, presumably a chymase, although other enzyme pathways exist. Preliminary data indicate that the non-ACE pathway may be substantially larger in disease states such as diabetes mellitus. One implication of the studies is that at the tissue level, Ang II antagonists have much greater potential for blocking the renin-angiotensin system than does ACE inhibition-with implications for therapeutics.
...
PMID:Pathways for angiotensin II generation in intact human tissue: evidence from comparative pharmacological interruption of the renin system. 974 Jun

The natriuretic peptide (NP) system is one of the most important systems regulating blood pressure and body-fluid homeostasis. The biological activities of the system are determined by the NPs and the receptors, which are comprised of three subtypes: NP-AR and NP-BR related to biological activities and NP-CR related to the clearance of NP. We focused our studies on the receptor subtypes. In hypertensive rats (SHR-SP/Izm, DOCA/salt), NP-AR was upregulated and NP-CR was downregulated. The ACE inhibitor derapril, but not the Ca2+ blocker manidipine, normalized the upregulated NP-AR, but the effect was completely abolished by the bradykinin beta 2-receptor antagonist, suggesting that bradykinin regulates the vascular NP-AR. The AT1 antagonist TCV-116, but not manidipine, reversed the downregulated NP-CR. Ang II decreased NP-CR in cultured aortic smooth muscle cells. These results suggest that upregulation of NP-AR and downregulation of NP-CR with the increased plasma NPs counteract hypertension by enhancing the action of NP. A beta-blocker (carvedilol) potentiated the hypotensive action of NPs by increasing plasma NPs and enhancing the vascular response to NPs via downregulation of the vascular and lung NP-CR. The newly found mode of actions could be related to its anti-heart failure effect. In genetically hyperglycemic Wistar fatty rats, vascular NP-BR and NP-AR were upregulated. Since plasma ANP and vascular CNP were significantly increased, the local CNP/NP-BR system as well as the systemic ANP/NP-AR system may play an important role in counteracting vascular remodeling in diabetes mellitus. All these observations provide in vivo evidence for the pathophysiological significance of the receptor subtype of the NPs.
...
PMID:[Pathophysiological significance of the natriuretic peptide system: receptor subtype as another key factor]. 979 68

The range of known actions of amylin are reviewed together with the proposal that an important role for amylin may be the hormonal integration of diverse physiological systems activated with feeding. Major targets for the action of amylin are found within the kidney. Components of the amylin system (AS) have been shown to influence the activity of components of the renin-angiotensin system (RAS), and vice versa, in normal, hypertensive and diabetic models. For instance, amylin injected into humans and rats elicits a rapid rise in plasma renin activity. Furthermore, in two models of hypertension (the spontaneously hypertensive rat (SHR) and the model with subtotal nephrectomy (STNx)), the density of amylin-binding sites in the renal cortex associated with the proximal tubules, was associated with elevation of blood pressure. In normotensive controls and in the STNx model, but not in the SHR model, treatment with angiotensin-converting enzyme (ACE) inhibitors reduced blood pressure and the density of amylin binding in the renal cortex. In Sprague-Dawley rats, angiotensin II (Ang II) infusion was associated with increased density of amylin-binding sites as well as elevated blood pressure. Thus, there appears to be a direct relationship between the activity of Ang II and the binding sites for amylin in the renal cortex. From these studies it has been postulated that the activation of the AS in the kidney may play a role in the genesis and/or development of hypertension in certain contexts. The transient expression of amylin mRNA has been detected perinatally, using in situ hybridization, in the subnephrogenic zone of the metanephros and is associated with proximal tubules of the developing nephron. These cells situated close to the glomeruli, represent a subset of brush border epithelial cells. Amylin immunoreactivity (IR) is also found in these cells and colocalizes with angiotensinogen IR. Thus a second important role for amylin is described in which it plays a role as a growth factor in the developing kidney and in renal regrowth in the adult kidney. In a model of IDDM (streptozotocin diabetes), amylin and angiotensinogen IR are both restricted to a subset of brush border epithelial cells close to glomeruli which, in the developing kidney, expressed amylin mRNA. Thus in this IDDM model, we hypothesize that amylin mRNA transcription which is normally downregulated in the adult, is upregulated in this subset of these brush border epithelial cells, and that it stimulates the activity of a local RAS by an intracellular mechanism, leading to the biosynthesis of Ang II. It remains to be determined that if amylin is playing a role in stimulating local Ang II production at these sites, this provides a mechanism for activation of TGF-beta, ultimately leading to interstitial fibrosis.
...
PMID:Interaction of the renal amylin and renin-angiotensin systems in animal models of diabetes and hypertension. 993 Mar 78

Diabetic nephropathy often co-exists with other manifestations of microangiopathy, in particular retinopathy. Recent clinical evidence suggests that inhibition of the renin-angiotensin system in humans can delay the development and/or progression of diabetic nephropathy and perhaps also retinopathy. The benefits of this therapeutic strategy may in part be explained by inhibition of the nonhaemodynamic actions of angiotensin II (Ang II). The recognized nonhaemodynamic actions of Ang II include the augmented release of many growth factors. Ang II can stimulate the release of vascular endothelial growth factor (VEGF) from human vascular tissues. VEGF is a family of potent cytokines which act to induce angiogenesis and markedly increase microvascular permeability. VEGF is abundantly expressed in the renal glomerulus, specifically within the podocyte, where its function is unknown. VEGF is also expressed in the retina and increased retinal VEGF expression occurs in diabetes and has been implicated in the pathogenesis of diabetic retinopathy. This review considers the potential clinical significance of Ang II-induced VEGF expression, if any, in the pathogenesis of diabetic nephropathy and retinopathy.
...
PMID:A potential role for angiotensin II-induced vascular endothelial growth factor expression in the pathogenesis of diabetic nephropathy? 993 Mar 79

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.
...
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.
...
PMID:Angiotensin II signaling in vascular smooth muscle cells under high glucose conditions. 993 Nov 33

We have recently reported a combination of renal features that suggests independent angiotensin-mediated control of the renal circulation in the majority of hypertensive patients with type II diabetes. To ascertain whether other tissue elements of the renin-angiotensin-aldosterone system (RAAS) also were activated, we examined the adrenal response to angiotensin II (AngII) infusion on a low salt diet. We assessed also the renin response to the upright position in patients on a low salt diet and renin suppression in patients on a high salt diet. We compared responses in 42 hypertensive patients with type II diabetes (53.1 +/- 1.4 years, mean +/- SEM), 25 healthy controls (52.6 +/- 4.4 years); and 137 essential hypertensives without diabetes (43.3 +/- 1.2 years). A low renin state, defined as a plasma renin activity (PRA) <2.5 ng angiotensin I (AI)/mL/h after 5 to 7 days on a 10-mmol Na diet and 2 h of upright posture, was found in 21% of the essential hypertensives, but in only 14% of patients with type II diabetes. On this diet, PRA increased from 2.7 +/- 0.4 supine to 10.1 +/- 1.3 ng AI/mL/h upon standing in healthy subjects. In patients with type II diabetes, PRA was 3.6 +/- 0.4 and increased to 9.1 +/- 1.0 ng AI/mL/h. On a high salt (200 mmol) diet, healthy subjects showed the expected PRA suppression (0.3 +/- 0.1), but in patients with type II diabetes the PRA was less suppressed (1.2 +/- 0.3 ng AI/mL/h; P = .003). Thus, in most hypertensive patients with type II diabetes the RAAS shows normal activation, but is poorly suppressible. AngII infused intravenously to assess adrenal responsiveness in patients on a low salt diet caused an essentially identical increase in aldosterone concentration in patients with type II diabetes (21.1 +/- 1.7 to 44.0 +/- 5.9 ng/dL) and in essential hypertension (20.6 +/- 1.4 to 43.7 +/- 2.8 ng/ dL). The frequency of nonmodulation assessed as a blunted adrenal response to AngII infusion was identical in type II diabetes (47%) and in essential hypertension (46%) after exclusion of the low renin patients. Thus, at the level of one tissue renin system, the adrenal glomerulosa, responses were unaltered in patients with type II diabetes. The relative unresponsiveness of the renal blood supply to infused AngII in type II diabetes in association with an enhanced renal vasodilator response to angiotensin converting enzyme inhibition probably reflects local, intrarenal actions secondary to the diabetic state. The infrequency of a low renin state, and the inappropriately high renin levels on a high salt intake, provide a rational basis for pharmacologic interruption of the renin system to treat patients with type II diabetes.
...
PMID:The state and responsiveness of the renin-angiotensin-aldosterone system in patients with type II diabetes mellitus. 1023 94

Angiotensin II (AII) acts by 2 types of receptors: the ATI receptor which mediates its actions on vasoconstriction, renin (inhibition) and aldosterone (stimulation) secretions, cellular proliferation and angiogenesis and the non-AT1 (often called AT2) receptors. Mainly expressed in the embryon these latter may favor cellular differentiation and recruitment of collateral circulation. Angiotensin converting enzyme inhibitors (ACEI) decrease the synthesis of All and therefore the stimulation of both receptor types whereas AT1-receptor antagonists (AT1RA) block only the stimulation of these latter and increase the stimulation of AT2 receptor since they increase the production of All secondarily to the inhibition of the feedback of renin secretion by All. Experimentally ACEI and AT1RA decrease angiogenesis and cellular proliferation and favor cellular differentiation which could explain the protective effect of ACEI against cancer suggested recently in a Scotish study. Despite of their common suppressive effect on angiogenesis AT1RA may better than ACEI protect against ischemic events specially the cerebral ones because they favor the rapid recruitment of collateral circulation. This has been demonstrated for losartan in case of abrupt ligation of the carotid in the gerbil since its previous administration protects against fatal cerebral ischemia whereas its previous administration with enalapril abolishes this protection. These data may explain why, in the CAPP trial, captopril which has prevented more effectively diabetes occurrence could not be proved superior to diuretics and/or betablocker in the prevention of myocardial infarction and specially of strokes for which exist on the contrary a suspicion of a lower protection. Therefore a comparative trial between AT1RA and ACEI in the prevention of stroke recurrence should appear as a priority for Public Health and Pharmaceutical Industry Authorities.
...
PMID:[Duality of angiotensin II receptors and risk for stroke and cancer: what is the connection?]. 1036 Jan 91

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>