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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a previous study, we demonstrated that doxazosin (DZN), an alpha(1)-adrenergic blocker, prevented proteinuria in streptozotocin diabetic rats. In this study, we investigated whether DZN would lower established proteinuria by improving glomerular sclerosis in spontaneously hypertensive corpulent rats with type 2 diabetes mellitus. DZN treatment was compared with treatment with angiotensin-converting enzyme inhibitor, lisinopril (LIS) alone, and DZN in combination with LIS. Combination therapy was used to examine any additive effect of either drug alone in the reduction of proteinuria and glomerular sclerosis. Both male and female rats age 6 months with established proteinuria were used. The rats were allocated randomly to 1 of 4 groups: untreated, DZN treated, LIS treated, or a combination of DZN and LIS treatment. Drug treatment was continued for 16 weeks. The results show that (1) either drug alone or in combination significantly lowered systolic blood pressure; (2) DZN, LIS, or combination therapy reduced albuminuria at 16 weeks of treatment from baseline by 38.61+/-5.77%, 30.70+/-4. 21%, and 42.17+/-4.77% (mean+/-SE), respectively. No difference in albuminuria was observed among the 3 groups of rats; (3) the fractional mesangial area, which was 20.55+/-3.77% in untreated rats, was significantly reduced to 11.18+/-1.32% in DZN-treated rats, with a further reduction to 8.72+/-0.64% in LIS-treated rats and to 3.48+/-0.35% in rats treated with DZN+LIS; and (4) DZN but not LIS significantly improved plasma glucose levels in spontaneously hypertensive corpulent rats (untreated 21.06+/-0.97 mmol/L versus DZN treated 15.81+/-0.93 mmol/L or DZN+LIS treated 17.38+/-1.10 mmol/L; P<0.025 to 0.005). Thus, the data suggest that 16-week treatment with either DZN or LIS improves established proteinuria and glomerular sclerosis, but combination therapy is superior to either DZN or LIS alone in preventing glomerular sclerosis in type 2 diabetic rats with hypertension.
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PMID:Effect of antihypertensive therapy on renal injury in type 2 diabetic rats with hypertension. 1094 83

DIVERSE KIDNEY DISORDERS: Patients with type 2 diabetes mellitus who develop nephropathy can have various types of disorders capable of progressively destroying the kidneys. It is now clear that the same type of diffuse or nodular glomerulosclerosis develops irrespective of the type of diabetes, i.e. the pathophysiology of hyperglycemia. HETEROGENEITY: There is however a certain degree of heterogeneity in terms of clinical presentation, clinical course and response to treatment. Heterogeneity is due to age, the number of different accumulated risk factors and disease states, genetic factors that are in the process of being identified, and finally, lesions to the urologic apparatus, the arteries, and the renal parenchyma itself that are not directly caused by diabetes. PRACTICAL IMPACT: Mixed lesions, due to both diabetic and non-diabetic causes, may therefore exist in the same kidney. These different possibilities should be systematically considered in order to adopt an individualized investigative and therapeutic attitude for each new patient.
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PMID:[Heterogeneity of nephropathies in type 2 diabetes]. 1124 30

CS-866 is a new angiotensin II receptor blocker that has demonstrated effectiveness for lowering blood pressure in animal models of hypertension. Given the proposed involvement of the renin-angiotensin system in diabetic nephropathy and atherosclerosis, we have tested CS-866 in animal models of these conditions. The renal protective properties of CS-866 were examined in the Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes that develops progressive hyperglycemia, glomerulosclerosis, and proteinuria. Treatment of ZDF rats with CS-866 in the diet for 19 weeks resulted in a dose-dependent reduction in urinary protein excretion compared with vehicle-treated control rats, which was independent of changes in blood pressure and glycemic state. The antiatherosclerotic properties of CS-866 were tested in 2 animal models. In the first study, cynomolgus monkeys were fed a high-cholesterol diet for 6 months while receiving CS-866 or vehicle. At the end of this period, CS-866-treated animals had 64% less plaque area in the aorta than controls. CS-866 was also tested in the Watanabe heritable hyperlipidemic (WHHL) rabbit model of atherosclerosis. WHHL rabbits were treated for 32 weeks with CS-866 (1 mg/kg), pravastatin (50 mg/kg), a combination of the 2 drugs, or vehicle. CS-866 had no effect on plasma cholesterol levels and reduced blood pressures minimally. Pravastatin alone reduced serum cholesterol but had no effect on blood pressure or lesion area. In contrast, treatment with CS-866 resulted in a 40% reduction in lesion area compared with vehicle-treated control when given alone and a 50% reduction in combination with pravastatin. On the basis of results from animal models, CS-866 may be a useful treatment for diabetic nephropathy and atherosclerosis.
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PMID:New pharmacologic aspects of CS-866, the newest angiotensin II receptor antagonist. 1133 66

Activation of the renal transforming growth factor-beta (TGF-beta) system likely mediates the excess production of extracellular matrix in the diabetic kidney. To establish the role of the TGF-beta system in type 2 diabetic nephropathy, we examined the intrarenal localization and expression of the TGF-beta1 isoform, the TGF-beta type II receptor, and the Smad signaling pathway in the 16-week-old db/db mouse, a genetic model of type 2 diabetes that exhibits mesangial matrix expansion, glomerular basement membrane thickening, and renal insufficiency that closely resemble the human disease. Compared with its nondiabetic db/m littermate, the db/db mouse showed significantly increased TGF-beta1 mRNA expression by in situ hybridization in both glomerular and tubular compartments. Likewise, TGF-beta1 protein, by immunohistochemical staining, was increased in both renal compartments, but the fractional expression of TGF-beta1 protein was less than that of the mRNA in the glomerulus. In situ hybridization and immunohistochemical staining for the TGF-beta type II receptor revealed concordant and significant increases of both mRNA and protein in the glomerular and tubular compartments of diabetic animals. Finally, immunohistochemistry showed preferential accumulation of Smad3 in the nuclei of glomerular and tubular cells in diabetes. The complementary technique of Southwestern histochemistry using a labeled Smad-binding element demonstrated increased binding of nuclear proteins to Smad-binding element, indicating active signaling downstream of the TGF-beta stimulus. We therefore propose that the TGF-beta system is up-regulated at the ligand, receptor, and signaling levels throughout the renal cortex in this animal model of type 2 diabetes. Our findings suggest that the profibrotic effects of TGF-beta may underlie the progression to glomerulosclerosis and tubulointerstitial fibrosis that characterize diabetic nephropathy.
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PMID:Increased glomerular and tubular expression of transforming growth factor-beta1, its type II receptor, and activation of the Smad signaling pathway in the db/db mouse. 1133 63

We have previously demonstrated that antihypertensive treatment with doxazosin (DZN), an alpha-adrenergic blocker, and lisinopril (LIS), an ACE inhibitor, reverse glomerular sclerosis in corpulent spontaneously hypertensive rats with type 2 diabetes. In this study, we examined the effects of the above-mentioned antihypertensive drugs alone and in combination on the structure of interlobular and arcuate arteries in these rats. Both male and female rats aged 6 months were treated with antihypertensive drugs for 16 weeks. Various structural parameters were evaluated by light microscopy, with the use of digital image analysis, in kidney sections stained with periodic acid-SCHIFF: Systolic blood pressure was significantly lower in treated than in untreated rats. Untreated diabetic rats had a significantly higher media/lumen ratio (smaller luminal diameter) of both arteries compared with the ratio in treated rats (for interlobular artery, 0.72+/-0.06 [no treatment], 0.49+/-0.03 [DZN treatment], 0.54+/-0.06 [LIS treatment], and 0.52+/-0.04 [combination therapy], P<0.05 to <0.001 for no treatment versus treatment; for arcuate artery, 0.66+/-0.11 [no treatment], 0.40+/-0.02 [DZN treatment], 0.39+/-0.04 [LIS treatment], and 0.40+/-0.03 [combination therapy], P<0.05 for no treatment versus treatment). Antihypertensive treatment caused significant increases in total arterial cross-sectional area, internal and external diameters, luminal and medial cross-sectional area, and medial thickness in both interlobular and arcuate arteries. The improvement in arterial structure after antihypertensive treatment was due to remodeling and growth of the vessels. Both DZN and LIS were equally efficacious, and combination therapy had no additive or synergistic effect.
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PMID:Effect of antihypertensive therapy on renal artery structure in type 2 diabetic rats with hypertension. 1135 40

Diabetic Nephropathy (DN) is the commonest cause of end-stage renal failure (ESRF) in the Western world. Diabetic nephropathy follows a well outline clinical course, starting with microalbuminuria through proteinuria, azotaemia and culminating in ESRF. Before the onset of overt proteinuria, there are various renal functional changes including renal hyperfiltration, hyperperfusion, and increasing capillary permeability to macromolecules. Basement-membrane thickening and mesangial expansion have long been recognized as pathological hallmark of diabetes. It has been postulated that DN occurs as a result of the interplay of metabolic and hemodynamic factors in the renal microcirculation. There is no doubt that there is a positive relationship between hyperglycaemia, which is necessary but not sufficient, and microvascular complications. The accumulation of advanced glycosylated end-products (AGEs), the activation of isoform(s) of protein kinase C (PKC) and the acceleration of the aldose reductase pathway may explain how hyperglycemia damages tissue. PKC is one of the key signaling molecules in the induction of the vascular pathology of diabetes. The balance between extracellular matrix production and degradation is important in this context. Transforming growth factor-beta (TGF-beta) appears to play a pivotal role in accumulation in the diabetic kidney. Hemodynamic disturbances are believed to be directly responsible for the development of glomerulosclerosis and its attendant proteinuria. There is familial clustering of diabetic kidney disease. A number of gene loci have been investigated to try to explain the genetic susceptibility to diabetic nephropathy. The genes coding for components of renin-angiotensin system have drawn special attention, due to the central role that this system plays in the regulation of blood pressure, sodium metabolism, and renal hemodynamics. Endothelial dysfunction is closely associated with the development of diabetic retinopathy, nephropathy and atherosclerosis, both in IDDM and in NIDDM. The pathogenesis of diabetic nephropathy is not clarified completely yet.
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PMID:Pathogenesis of diabetic nephropathy. 1146 May 89

Details of renal structural changes and structural-functional relationships at the early stage of diabetic nephropathy (DN) in type 2 diabetes are not well known. The present review focuses on these topics from previous studies using light and electron microscopic morphometric analysis. Glomerular hypertrophy, one of the histological changes in DN, is present in type 2 as well as in type 1 diabetic patients. However, mechanisms of increased glomerular size might be different from those in type 1 diabetes. Other typical glomerular changes, glomerular basement membrane thickening and mesangial expansion, are present in normoalbuminuric type 2 diabetic patients as a group. However, these parameters are similar between normo- and microalbuminuric patients. Renal structural-functional relationships cannot be seen in type 2 diabetic patients and therefore urinary albumin might not be a reliable indicator for glomerular structural changes in type 2 diabetic patients. Although previous reports showed reversibility of advanced diabetic glomerulosclerosis in type 1 diabetes by 10 years of strict glycemic control, there is no report regarding histological reversibility by therapeutic interventions in type 2 diabetic patients. In addition, it is unclear whether DN lesions are concordant or discordant with diabetic retinopathy grade in type 2 diabetes. From this information, renal structural changes or structural-functional relationships in type 2 diabetic patients might be heterogeneous and different from those in type 1 diabetic patients. Careful longitudinal study of renal structure and function including serial renal biopsy at the early stage of DN in type 2 diabetes is necessary.
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PMID:Glomerular structural changes and structural-functional relationships at early stage of diabetic nephropathy in Japanese type 2 diabetic patients. 1181 Apr 68

We report an 85 years-old patient with type 2 diabetes mellitus and both clinical and biochemical nephrotic syndrome. The renal biopsy showed membranous nephropathy at stage I-II. There was no evidence of malignancy. The patient was treated with steroids, and two months later the proteinuria had not improved. The objects under discussion are the factors that should lead to suspect the existence of glomerulonephritis, other than diabetic glomerulosclerosis, suggesting the need for kidney biopsy. We also focus on the prognostic and therapeutic relevance, as well as on the common pathogenic aspects.
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PMID:[Idiopathic membranous nephropathy in an elderly patient with type 2 diabetes mellitus]. 1181 18

The frequency of various types of renal changes in patients with type 2 diabetes is not clearly defined in the literature. Reported discrepancies likely are caused by ethnic and geographic factors. However, policies used in nephrological centers for the selection of patients to undergo renal biopsy also may have an influence. The present study reports 393 renal biopsies in patients with type 2 diabetes performed in a group of centers in northwestern Italy using different (restricted [CRPs] or unrestricted [CUP]) biopsy policies. On the basis of light microscopic, immunofluorescence, and ultrastructural findings, cases were subdivided into three classes characterized by the presence of diabetic glomerulosclerosis (class 1), prevailing vascular (arterioarteriolosclerotic) and ischemic glomerular changes (class 2), other glomerulonephritides superimposed on diabetic glomerulosclerosis (class 3a), or glomerulonephritides without the presence of diabetic glomerulosclerosis (class 3b). Although no significant differences were found for class 2 (detected in 15% and 16% of patients from CRPs and the CUP, respectively), the frequency of the other two classes was strongly biased by the biopsy policy. Class 1 was found in 29% and 51% of cases, and class 3 in 57% and 33% of cases from CRPs and the CUP, respectively. Moreover, class 3a was more common (67%) in the CUP, and class 3b (78%) in CRPs. Our findings may explain conflicting data from the literature and the influence that type of adopted biopsy policy may have on an epidemiological evaluation. This study helps clarify the frequency of renal changes in patients with type 2 diabetes and suggests more extensive use of renal biopsy to obtain reliable prognostic indications and plan a rational therapeutic approach.
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PMID:Different patterns of renal damage in type 2 diabetes mellitus: a multicentric study on 393 biopsies. 1192 Mar 36

There is a unique relationship between the kidney and blood pressure (BP): on the one hand, renal dysfunction and particularly renal disease cause an increase in BP, while on the other hand, high BP accelerates loss of function of the diseased kidney. Transplantation studies, both in experimental animals and humans, documented that "blood pressure goes with the kidney," a normotensive recipient of a kidney genetically programmed for hypertension (HT) will develop HT, while conversely hypertensive patients with renal failure receiving the kidney of a normotensive donor may develop normotension. Family studies showed higher BP values and more frequent HT in first degree relatives of patients with primary glomerulonephritis or diabetic nephropathy, both type 1 and type 2. The notion that HT accelerates the loss of renal function has been proposed at the turn of the century, but definite evidence by observational and interventional studies has only been provided in the last two decades. The issue has been much confounded by the mistaken believe that damaged kidneys require higher BP values in order to function properly. The mechanisms of BP increase in renal disease comprise: salt retention, inappropriate activity of the renin-angiotensin system (RAS) and of the sympathetic nerve system as well as impaired endothelial cell-mediated vasodilatation. There is ample evidence both in primary renal disease (AIPRI and REIN trials) and in nephropathy of type 1 and type 2 diabetes (IDNT, RENAAL) that pharmacological blockade of the RAS by angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers has BP-independent renoprotective effects. More recently, it has also been shown that blockade of the sympathetic nerve system has BP-independent effects on albuminuria and on glomerulosclerosis.
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PMID:Kidney and hypertension. 1198 15


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