Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypervolemia is considered to play a major role in the pathogenesis of diabetic vasculo- and nephropathy. The aim of our study is to determine whether children and adolescents with insulin-dependent diabetes mellitus (IDDM) experience alterations in blood volume (BV) before onset of apparent nephropathy. BV (calculated as the sum of measured plasma volume (PV) and red cell volume (RCV)) was determined in 31 children (9-16 yr) with a mean duration of IDDM of 6.6 yr and without microalbuminuria. Due to dependence of these values on age, size and sex, all data were normalised for body size parameters. While no statistical difference for BV normalised for lean body mass (LBM) (86.98+/-9.5 ml/kg) was found in diabetic children compared with our control population (84.91+/-12.08 ml/kg), a difference could be shown when normalised for body surface area (BSA) (diabetic children 2.37+/-0.3 L/m(2); control population 2.15+/-0.38 L/m(2), p=0.002). Increased BV is only present when normalising for BSA and not for the theoretical superior LBM-index. Because the study population exhibited a poor glycemic control (HbA1c 10.2+/-2.4 %), an influence of glucosuria-induced polyuria on BV cannot be excluded. Taking into account these limitations our data do not confirm the presence of hypervolemia before onset of diabetic nephropathy.
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PMID:Lack of evidence of hypervolemia in children with insulin-dependent diabetes mellitus. 1711 99

The objective is to assess the effect of TNF-alpha inhibition on urinary albumin excretion in experimental diabetic rats. Male Wistar rats, 8-week-old, were categorized into four groups, which were the control (n = 9), diabetes (n = 9), infliximab-treated diabetes (n = 10), and FR167653-treated diabetes (n = 9) groups. Diabetes was induced by intraperitoneal injection of STZ (40 mg/kg). Thereafter, infliximab was injected intraperitoneally once a month (5.5 mg/kg) and FR167653 was administered orally by mixing with the rat chow (0.08%). The effects of infliximab and FR167653 on urinary albumin excretion were observed for 12 weeks. Body weight, blood sugar, 24-h urinary TNF-alpha, and 24-h urinary albumin/creatinine ratio (Ualb/Ucr) levels were determined at 1, 4, 8, and 12 weeks after the STZ-injection. Treatment of rats with STZ caused a significant loss of body weight, as well as polyuria and hyperglycemia within 1 week, while the urinary excretions of albumin and TNF-alpha were increased. Neither infliximab nor FR167653 affected body weight or blood sugar levels, whereas both decreased urinary albumin excretion, together with a modest decrease in the urinary excretion of TNF-alpha. These results suggest a role of TNF-alpha in the pathogenesis of diabetic nephropathy and show that TNF-alpha inhibition is a potential therapeutic strategy.
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PMID:Effect of TNF-alpha inhibition on urinary albumin excretion in experimental diabetic rats. 1776 70

The effects of long-term diabetes in the presence of established nephropathy on tubular function remains poorly understood. We evaluated the levels of the main sodium and water transport proteins expressed in the kidney after long-term (8 weeks) of streptozotocin (STZ)-induced type 1 diabetes mellitus (DM) in untreated (D) and insulin (4 U/s.c./day)-treated (D+I) rats. D animals presented upregulation ( approximately 4.5-fold) of Na/glucose cotransporter (SGLT1), whereas the alpha-subunit of the epithelial sodium channel (alpha-ENaC) and aquaporin 1 (AQP1) were downregulated ( approximately 20 and 30% respectively) with no change in the Na/H exchanger (NHE3), Na/Cl cotransporter (TSC) and AQP2. Insulin replacement partially prevented these alterations and caused increases in the expression of alpha-ENaC and AQP2. These effects suggest an action of insulin in the tubular transport properties. The upregulation of SGLT1 may constitute a mechanism to prevent greater glucose losses in the urine but it may result in glucotoxicity to the proximal epithelial cells contributing to the diabetic nephropathy. The decrease of alpha-ENaC in D animals may compensate for the increased sodium reabsorption via SGLT1 resulting in discrete natriuresis. DM-induced polyuria was not due to changes in AQP2 expression.
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PMID:Effect of long-term type 1 diabetes on renal sodium and water transporters in rats. 1794 18

Diabetic nephropathy is one of the major complications of diabetes. Oxidative stress is implicated as an important mechanism by which diabetes causes nephropathy. The aim of the study was to examine the involvement of oxidative stress in the progression of nephropathy in STZ diabetic animals and to evaluate the potential of polyphenolic extract (PPE) in the treatment of diabetes mellitus. In this study, we examined whether prolonged oral administration of polyphenolic extract of Ichnocarpus frutescens could prevent the progress or improve the outcome of diabetic nephropathy induced by oxidative stress in STZ diabetic rats. Intraperitoneal glucose tolerance test (IPGTT) revealed a significant decrease in blood glucose levels at 180 min after glucose loading in Wistar albino rats fed with PPE. During the eight weeks of experimental period, diabetic rats exhibited wide range of symptoms, including loss of body weight, hyperglycemia, polyuria, proteinuria, renal enlargement, and total renal dysfunction. A significant increase in TBARS level was observed in diabetic kidney, which was accompanied by a significant decrease in enzymatic and non-enzymatic antioxidant levels. After eight weeks, PPE-treated groups showed a lower level of blood glucose compared with non-treated STZ diabetic rats. The increases in urinary albumin and protein after eight weeks of treatment were significantly inhibited by prolonged treatment with PPE. In addition, PPE attenuates the adverse effects on hepatic biomarkers. We found that PPE can effectively protect against aldose reductase activity and protein damage (albumin glycation), and showed that its action was mainly due to enriched polyphenolic content. Our results also showed that treatment with PPE normalized the increase in hyperalgesia (i.e., the response to thermal stimuli) associated with the induction of diabetes by STZ. PPE administration in diabetic rats clearly ameliorated diabetic complications, suggesting not only a natural antioxidant but also supportive therapy for the treatment of type II diabetes.
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PMID:Polyphenolic extract of Ichnocarpus frutescens attenuates diabetic complications in streptozotocin-treated diabetic rats. 1835 Apr 51

Tubulo-interstitial pathology in diabetic nephropathy is thought to be caused by cell injury that is induced by high ambient glucose levels and increased proportions of glycated proteins. Other mechanistic hypotheses engage glomerular ultrafiltration of proteins and bioactive growth factors and their effects on tubular cells. Some scholars promote tubular ischaemia due to reduced peritubular blood flow as a response to glomerular injury. All of these mechanisms contribute to renal tubulo-interstitial injury in diabetic nephropathy. However, they do not well explain observations that have been made in studies of experimental animals and evaluations of human biopsies showing dilated collecting ducts in early diabetic nephropathy. Dilatation of distal nephron segments is routinely seen in human biopsies or in histological sections from experimental diabetic nephropathy and is reminiscent of similar findings in obstructive nephropathy. Moreover, it is these dilated tubules that are the primary source for pro-inflammatory and pro-fibrogenic cytokines and regulators. Based on this large body of observations from this laboratory and the published literature this narrative develops a novel hypothesis where hyperglycaemic, osmotic polyuria play important contributory roles in the initiation and progression of tubulo-interstitial injury in diabetic nephropathy.
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PMID:Osmotic polyuria: an overlooked mechanism in diabetic nephropathy. 1845 80

Type 2 diabetes is associated with obesity, insulin resistance, hyperglycemia, hyperphagia, polyuria, body weight gain, excessive secretion of glucocorticoids (GCs), thymus involution, adrenal gland hypertrophy, diabetic nephropathy, etc. We examined the effect of cerebrocrast, a new antidiabetic agent (synthesized in the Latvian Institute of Organic Synthesis), on body weight, food and water intake, urine output, and on changes of organ weight: that is, kidney, thymus, adrenal gland of normal rats. Cerebrocrast was administered at doses of 0.05 and 0.5 mg kg(-1) per os (p.o.) once a day for three consecutive days, and its effects were observed from 3 to 27 days after the last administration. Cerebrocrast, during the experimental period, decreased body weight by an average of approximately 32.3%, food intake by about 10-15% at the beginning of the experiments and by 22.6% at the end of the experiments, especially at a dose of 0.5 mg kg(-1). Water intake and urine output in comparison with controls were decreased. The daily food intake decreased about 1.0 and 2.1 g by administering single cerebrocrast doses of 0.05 and 0.5 mg kg(-1) body weight (b.w.), respectively, but by administering for three consecutive days, food intake decreased by about 2.2 and 3.4 g, respectively. The weekly body weight gain decreased by administering a single dose of cerebrocrast by 2.61 and 2.51 g, respectively, and by triple administration it decreased by 4.36 and 3.07 g, respectively. Cerebrocrast has long-lasting effects on these parameters and on thymus and adrenal gland weight. As cerebrocrast decreased glucose levels in normal and streptozotocin (STZ)-induced diabetic rats, it also promoted glucose uptake by the brain, intensified insulin action and formation de novo of insulin receptors. We can conclude that cerebrocrast may regulate food intake and body weight through glucose sensing by proopiomelanocortin (POMC) neurons, that are involved in control of glucose homeostasis, stimulation of alpha-melanocyte-stimulating hormone (alpha-MSH) secretion, activation of MC4-Rs and inhibition of neuropeptide Y (NPY) in the ARC of the hypothalamus, affecting the kidney, and causing decreased urine output and water intake. Moreover, it could stimulate secretion of vasopressin. By administration of cerebrocrast thymus mass was increased, thereby preventing the action of GCs. As cerebrocrast inhibited L- and T-type calcium channels, it can prevent vasoconstriction of kidney arterioles and aldosterone secretion that have significant roles in the development of hypertension and diabetic nephropathy. These properties of cerebrocrast are important for treatment of Type 2 diabetes and its consequent development of hypertension and diabetic nephropathy.
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PMID:Effect of cerebrocrast on body and organ weights, food and water intake, and urine output of normal rats. 1903 18

Degradation of extracellular matrix (ECM) by enhanced production of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in diabetes leads to nephropathy. Cyclooxygenases (COX) further increase levels of these MMPs. The objective of present study was to inhibit MMP-2 and MMP-9 by combination of minocycline and aspirin to treat diabetic nephropathy. Diabetes was induced in male Wistar rats by streptozotocin (STZ, 55 mg/kg i.p.). Four weeks after diabetes induction, the rats were treated with minocycline (50 mg/kg, p.o.), aspirin (50 mg/kg, p.o.), or minocycline (50 mg/kg, p.o.) plus aspirin (50 mg/kg, p.o.) for a period of 4 weeks. At the end of eighth week fluid input, urine output, and renal function tests were carried out for diagnosis of diabetic nephropathy. Renal hypertrophy was measured and histopathology was done to evaluate renal damage. Diabetes produced significant loss of body weight, polyuria, polydipsia, hyperglycemia, and increase in blood pressure. Serum creatinine, urea, and blood urea nitrogen levels were found to be increased significantly in the STZ group diabetic rats. Treatment with combination of minocycline and aspirin significantly prevented the rise in creatinine, urea, and blood urea nitrogen levels and increased creatinine clearance. Image analysis of kidneys revealed that collagen level was significantly decreased in combined treated group when compared with control. Results of present study suggest that MMP-2 and MMP-9 inhibition in presence of COX inhibitor prevents the development of experimental diabetic nephropathy in rats and can be a potential approach for the treatment.
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PMID:Minocycline with aspirin: an approach to attenuate diabetic nephropathy in rats. 2121 9

Diabetic nephropathy is a major "microvascular" complication of diabetes, differs from other causes of chronic kidney diseases in its predictability, with well-defined functional progression from hyperfiltration to micro- to macroalbuminuria to renal failure. The present study was undertaken to investigate the effect of Asparagus racemosus Willd (Liliaceae) on streptozotocin-induced early diabetic nephropathy. Single i.p injection of streptozotocin (55 mg/kg) was administered to induce early diabetic nephropathy in Wistar rats and thereafter treated orally with ethanolic extract of Asparagus racemosus (EEAR) at a dose level of 100 and 250 mg/kg daily for 4 weeks. The efficacy of extract was compared with diabetic control rats. A. racemosus treatment significantly decreased plasma glucose, creatinine, urea nitrogen, total cholesterol and triglyceride levels. Renal hypertrophy, polyuria, hyperfiltration, microalbuminuria and abnormal changes in the renal tissue as well as oxidative stress were effectively attenuated by EEAR treatment. Basement membrane thickening and mesangial proliferation formation without nodules were seen in diabetic rats, whereas these structural changes were reduced in EEAR treated groups. Results of this study suggested that A. racemosus has beneficial effect in the treatment of diabetic
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PMID:Asparagus racemosus Willd (Liliaceae) ameliorates early diabetic nephropathy in STZ induced diabetic rats. 2282 26

Effect of irbesartan, an angiotensin II receptor antagonist, was studied in streptozotocin (STZ) induced diabetic nephropathy. Polyuria, proteinuria, blood urea, creatinine clearance, and urinary electrolytes were determined to assess kidney damage. There was a significant increase in urine volume, urinary protein and blood urea in STZ induced diabetic rats. On the other hand, irbesartan treatment resulted in a significant reduction in urinary protein and blood urea in these rats. Irbesartan treatment also improved creatinine clearance and exhibited a natriuretic effect in these animals. Results suggest that irbesartan treatment ameliorate STZ induced diabetic nephropathic changes, in rats.
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PMID:Effect of irbesartan on streptozotocin induced diabetic nephropathy: An interventionary study. 2310 51

Dot1l encodes histone H3 K79 methyltransferase Dot1a. Mice with Dot1l deficiency in renal Aqp2-expressing cells (Dot1l(AC)) develop polyuria by unknown mechanisms. Here, we report that Aqp5 links Dot1l deletion to polyuria through Aqp2. cDNA array analysis revealed and real-time RT-qPCR validated Aqp5 as the most upregulated gene in Dot1l(AC) vs. control mice. Aqp5 protein is barely detectable in controls, but robustly expressed in the Dot1l(AC) kidneys, where it colocalizes with Aqp2. The upregulation of Aqp5 is coupled with reduced association of Dot1a and H3 dimethyl K79 with specific subregions in Aqp5 5' flanking region in Dot1l(AC) vs. control mice. In vitro studies in IMCD3, MLE-15 and 293Tcells using multiple approaches including real-time RT-qPCR, luciferase reporter assay, cell surface biotinylation assay, colocalization, and co-immunoprecipitation uncovered that Dot1a represses Aqp5. Human AQP5 interacts with AQP2 and impairs its cell surface localization. The AQP5/AQP2 complex partially resides in the ER/Golgi. Consistently, AQP5 is expressed in none of 15 normal controls, but in all of 17 kidney biopsies from patients with diabetic nephropathy. In the patients with diabetic nephropathy, AQP5 colocalizes with AQP2 in the perinuclear region and AQP5 expression is associated with impaired cellular H3 dimethyl K79. Taken together, these data for the first time identify Aqp5 as a Dot1a potential transcriptional target, and an Aqp2 binding partner and regulator, and suggest that the upregulated Aqp5 may contribute to polyuria, possibly by impairing Aqp2 membrane localization, in Dot1l(AC) mice and in patients with diabetic nephropathy.
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PMID:Aqp5 is a new transcriptional target of Dot1a and a regulator of Aqp2. 2332 16


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