Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously showed that the 12/15-lipoxygenase (12/15-LO) pathway of arachidonate acid metabolism is involved in multiple events related to diabetic nephropathy (DN), including glomerular hypertrophy and extracellular matrix deposition (Kang SW, Adler SG, Nast CC, LaPage J, Gu JL, Nadler JL, Natarajan R. Kidney Int 59: 1354-1362, 2001; Kang SW, Natarajan R, Shahed A, Nast CC, LaPage J, Mundel P, Kashtan C, Adler SG. J Am Soc Nephrol 14: 3178-3187, 2003; Kim YS, Lanting L, Adler SG, Natarajan R. Kindney Int 64: 1702-1714, 2003; Reddy MA, Adler SG, Kim YS, Lanting L, Rossi JJ, Kang SW, Nadler JL, Shahed A, Natarajan R. Am J Physiol Renal Physiol 283: F985-F994, 2002). In this study, we investigated whether in vivo delivery of small interfering RNAs (siRNAs) targeting 12/15-LO can ameliorate renal injury and DN in a streptozotocin-injected mouse model of type 1 diabetes. To achieve greater in vivo access and siRNA expression in the kidney, we used double-stranded 12/15-LO siRNA oligonucleotides conjugated with cholesterol. Diabetic DBA/2J mice were injected subcutaneously with either cholesterol-tagged 12/15-LO siRNA, mismatched control siRNA, or vehicle alone, twice weekly for 7 wk. Relative to controls, mice that received 12/15-LO siRNA showed significant reduction in albuminuria, kidney-to-body weight ratios, glomerular mesangial matrix expansion, renal structural damage, and monocyte/macrophage infiltration. These effects were associated with lower renal cortical or glomerular levels of profibrotic markers transforming growth factor-beta, connective tissue growth factor, type I and type IV collagens, plasminogen activator inhibitor 1, and fibronectin. The diabetes-induced increase in glomerular cyclin-dependent kinase inhibitors that are associated with hypertrophy was also prevented by siRNA administration. Our results show for the first time that systemic delivery of cholesterol-tagged siRNAs targeting 12/15-LO has renoprotective effects under diabetic conditions and therefore could be a novel therapeutic approach for DN.
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PMID:Effects of cholesterol-tagged small interfering RNAs targeting 12/15-lipoxygenase on parameters of diabetic nephropathy in a mouse model of type 1 diabetes. 1856 37

Diabetic cardiomyopathy can progress toward overt heart failure with increased mortality. The hexosamine biosynthesis pathway has been implicated in signaling for fibrosis by the kidney. Thiamine (vitamin B(1)) is an indispensable coenzyme and required at intracellular glucose metabolism. In this study, we assessed if decrease of flux through the hexosamine biosynthesis pathway induced by high-dose thiamine therapy counteracts diabetes-induced cardiac fibrosis. The diabetes model used was the streptozotocin-induced diabetic rat. Normal control and diabetic rats were studied for 2 weeks with and without thiamine, and followings were analyzed; plasma biochemicals (total cholesterol and triglycerides), morphological changes, mRNA abundance relevant to cardiac failure (brain natriuretic peptide) and fibrosis (transforming growth factor-beta1, thrombospondine, fibronectin, plasminogen activator-I and connective tissue growth factor) as well as and matrix metalloproteinase activity were investigated. Thiamine repletion prevented diabetes-induced cardiac fibrosis without changes in plasma glucose concentration. This was achieved by prevention of thiamine depletion, increased pro-fibrotic mRNA abundance and decreased metalloproteinase activity in the heart of diabetic rats. O-glycosylated protein was significantly higher in the left ventricular of diabetic rats compared to control rats, which was decreased by thiamine administration. Thiamine repletion prevented diabetes-induced cardiac fibrosis in experimental diabetes, probably by suppression of hexosamine biosynthesis pathway.
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PMID:Prevention of incipient diabetic cardiomyopathy by high-dose thiamine. 1882 45

The onset of diabetic nephropathy is characterised by a rise in albumin excretion rate (AER) and/or a transient rise in glomerular filtration rate (GFR) (hyperfiltration). Without intervention AER increases exponentially and there is a linear decrease in GFR after onset of overt nephropathy. In overt nephropathy, AER is a predictor of decline in GFR and the early AER response to antihypertensive therapy correlates with long-term decline in GFR. AER can be measured by immunoassay or by other techniques including HPLC. However, HPLC assays result in higher levels of AER in normal subjects compared with immunoassayable AER. Recent data suggest that there are distinct albuminuric and non-albuminuric pathways to renal impairment in type 1 and type 2 diabetes. In type 2 diabetes, the non-albuminuric pathway may explain a decline in GFR to <60 ml/min/1.73 m(2) in approximately one in four subjects after accounting for the use of renin angiotensin system inhibitors. In established nephropathy (chronic kidney disease (CKD) stages 3 and 4), plasma cystatin C based estimates of GFR are marginally superior to creatinine based estimates. However, cystatin C clearly outperforms creatinine based estimates of GFR decline at GFR levels >60 ml/min/1.73 m(2) (CKD stages 1 and 2). Other potential markers of progression of diabetic nephropathy include transforming growth factor beta (TGFbeta) and connective tissue growth factor (CTGF). However, long-term studies are needed to define their roles as markers of progression. Diabetic nephropathy is likely to be more susceptible to intervention at an early stage and accurate estimation of GFR is already possible with cystatin C. However, improved formulas for estimating GFR based on using creatinine or other markers are still required, because this may still provide the most cost effective approach applicable to existing clinical practice.
Diabetes Res Clin Pract 2008 Nov 13
PMID:New and old markers of progression of diabetic nephropathy. 1893 92

The effect of irbesartan on the expression of connective tissue growth factor (CTGF) and alpha-smooth-muscle actin (alpha-SMA) in the renal tubulointerstitium of diabetic rats was investigated in our study. Diabetes was induced in male Wistar rats by intraperitoneal administration of streptozotocin (STZ), 60 mg.kg(-1) body weight. The rats were then randomized to a diabetic group (DM) and an irbesartan therapy group (DM + Irb). The normal group (non-DM) rats were administered only citrate buffer. At the end of the 16th week, blood glucose, kidney weight/body weight, urine albumin (UAlb) and creatinine clearance rate were determined. The renal histopathology was observed by light microscopy. Further biochemical analysis of CTGF and alpha-SMA was provided using real-time reverse transcription PCR, immunostaining and Western blotting techniques. Compared with the non-DM group, blood glucose, kidney weight/body weight, UAlb, creatinine clearance and interstitial fibrotic lesions were increased in the DM group (p < 0.01). Treatment with irbesartan improved these parameters except blood glucose. Compared with the non-DM group, expressions of CTGF and alpha-SMA in the renal tubulointerstitium were highly upregulated in the DM group (p < 0.01). Administration of irbesartan prevented the high expressions of CTGF and alpha-SMA in renal tissue of diabetic rats. These results indicated that irbesartan can protect the kidney of STZ-diabetic rats by reducing the expression of CTGF and alpha-SMA in the renal tubulointerstitium.
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PMID:Irbesartan ameliorates diabetic nephropathy by reducing the expression of connective tissue growth factor and alpha-smooth-muscle actin in the tubulointerstitium of diabetic rats. 1906 61

Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of matricellular proteins. Its expression is induced by a number of factors including TGF-beta. It has been associated with fibrosis in various tissues including the kidney. Diabetic nephropathy (DN) develops in about 30% of patients with diabetes and is characterized by thickening of renal basement membranes, fibrosis in the glomerulus (glomerulosclerosis), tubular atrophy and interstitial fibrosis, all of which compromise kidney function. This review examines changes in CTGF expression in the kidney in DN, the effects they have on glomerular mesangial and podocyte cells and the tubulointerstitium, and how these contribute to driving fibrotic changes in the disease. CTGF can bind to several other growth factors modifying their function. CTGF is also able to interact with receptors on cells, including integrins, tyrosine receptor kinase A (TrkA), low density lipoprotein receptor-related protein (LRP) and heparan sulphate proteoglycans. These interactions, the intracellular signalling pathways they activate, and the cellular responses evoked are reviewed. CTGF also induces the expression of chemokines which themselves have pharmacological actions on cells. CTGF may prompt some responses by acting through several different mechanisms, possibly simultaneously. For example, CTGF is often described as an effector of TGF-beta. It can promote TGF-beta signalling by binding directly to the growth factor, promoting its interaction with the TGF-beta receptor; by triggering intracellular signalling on binding the TrkA receptor, which leads to the transcriptional repression of Smad7, an inhibitor of the TGF-beta signalling pathway; and by binding to BMP-7 whose own signalling pathway opposing TGF-beta is inhibited, leading to enhanced TGF-beta signalling.
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PMID:Connective tissue growth factor(CCN2), a pathogenic factor in diabetic nephropathy. What does it do? How does it do it? 1921 81

Diabetic nephropathy is characterized by decreased expression of bone morphogenetic protein-7 (BMP-7) and decreased podocyte number and differentiation. Extracellular antagonists such as connective tissue growth factor (CTGF; CCN-2) and sclerostin domain-containing-1 (SOSTDC1; USAG-1) are important determinants of BMP signaling activity in glomeruli. We studied BMP signaling activity in glomeruli from diabetic patients and non-diabetic individuals and from control and diabetic CTGF(+/+) and CTGF(+/-) mice. BMP signaling activity was visualized by phosphorylated Smad1, -5, and -8 (pSmad1/5/8) immunostaining, and related to expression of CTGF, SOSTDC1, and the podocyte differentiation markers WT1, synaptopodin, and nephrin. In control and diabetic glomeruli, pSmad1/5/8 was mainly localized in podocytes, but both number of positive cells and staining intensity were decreased in diabetes. Nephrin and synaptopodin were decreased in diabetic glomeruli. Decrease of pSmad1/5/8 was only partially explained by decrease in podocyte number. SOSTDC1 and CTGF were expressed exclusively in podocytes. In diabetic glomeruli, SOSTDC1 decreased in parallel with podocyte number, whereas CTGF was strongly increased. In diabetic CTGF(+/-) mice, pSmad1/5/8 was preserved, compared with diabetic CTGF(+/+) mice. In conclusion, in human diabetic nephropathy, BMP signaling activity is diminished, together with reduction of podocyte markers. This might relate to concomitant overexpression of CTGF but not SOSTDC1.
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PMID:BMP signaling and podocyte markers are decreased in human diabetic nephropathy in association with CTGF overexpression. 1925 50

We have demonstrated that Zn supplementation mediated up-regulation of cardiac metallothionein (MT) as a potent antioxidant prevented the development of diabetic cardiomyopathy. The present study was undertaken to test whether induction of renal MT synthesis by Zn supplementation protects the kidney from diabetes-induced damage. Streptozotocin-induced diabetic rats were treated with and without Zn supplementation at 5 mg/kg in drinking water for 3 months. Diabetic renal damage was detected by examining renal pathological alterations and 24-h urinary protein levels. Three-month Zn supplementation immediately after the onset of diabetes, partially but significantly, prevented the kidney from diabetes-induced increases in 24-h urinary proteins and pathological alterations. Diabetes-induced renal oxidative damage, inflammation and up-regulated expression of profibrosis mediator connective tissue growth factor (CTGF) were also markedly attenuated by Zn supplementation, along with significant increases in Zn levels concomitant with MT expression in renal tubular cells. Direct exposure of renal tubular (HK11) cells to high levels of glucose (HG) induced CTGF up-regulation predominantly through ERK (extracellular signal-regulated kinase)1/2-dependent, and partially through p38 mitogen-activated protein kinase (MAPK)-dependent pathways. Pretreatment of HK11 cells with Zn or cadmium induced MT expression and also significantly suppressed HG-induced CTGF expression. These results provide the first evidence for Zn supplementation to attenuate diabetes-induced renal pathological changes, likely through prevention of hyperglycemia-induced CTGF expression by Zn-induced MT in renal tubular cells.
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PMID:Zinc supplementation partially prevents renal pathological changes in diabetic rats. 1936 54

Total aralosides of Aralia elata (Miq) Seem (TASAES) from Chinese traditional herb Longya Aralia chinensis L was found to improve cardiac function. The present study was to determine the protective effects of TASAES on diabetic cardiomyopathy, and the possible mechanisms. Therefore, a single dose of streptozotocin was used to induce diabetes in Wister rats. Diabetic rats were immediately treated with low, medium and high doses of TASAES at 4.9, 9.8 mg/kg and 19.6 mg/kg body weight by gavage, respectively, for eight weeks. Cardiac function was evaluated by in situ hemodynamic measurements, and patch clamp for the L-type Ca2+ channel current I(Ca(2+)-L) and transient outward K+ channel current (I(to)). Histopathological changes were observed under light and electron microscope. The expression of pro-fibrotic factor, connective tissue growth factor (CTGF) was monitored using immunohistochemistry staining. Compared with diabetic group, medium and high doses, but not low dose, of TASAES showed a significant protection against diabetes-induced cardiac dysfunction, shown by increased absolute value of left ventricular systolic pressure (LVSP) and maximum rates of pressure development (+/-dp/dt(max)), and enhanced amplitude of I(Ca(2+)-L) (P<0.05). Histological staining indicated a significant inhibition of diabetes-caused pathological changes and up-regulation of CTGF expression (P< 0.05). The results suggest that TASAES prevents diabetes-induced cardiac dysfunction and pathological damage through up-regulating I(Ca(2+)-L) in cardiac cells and decreasing CTGF expression.
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PMID:Protective effect of total aralosides of Aralia elata (Miq) Seem (TASAES) against diabetic cardiomyopathy in rats during the early stage, and possible mechanisms. 1938 Oct 71

The aim of this study was to determine whether inner retinal dysfunction in diabetic rats is correlated with structural and/or biochemical changes in the retina and optic nerve. Using the electroretinogram (ERG; -5.83 to 1.28 log cd.s.m(-2)) retinal function (photoreceptor, bipolar, amacrine and ganglion cell components) was measured in control (n=13; citrate buffer) and diabetic (n=13; streptozotocin, STZ, 50 mg kg(-1)) rats, 12 weeks following treatment. Retinae and optic nerves were analyzed for structural changes and retinae were assessed for alterations in growth factor/cytokine expression using quantitative real-time PCR. We found that phototransduction efficiency was reduced 12 weeks after STZ-induced diabetes (-30%), leading to reduced amplitude of ON-bipolar (-18%) and amacrine cell (-29%) dominated responses; ganglion cell dysfunction (-84%) was more profound. In the optic nerve, nerve fascicle area and myelin sheath thickness were reduced (p<0.05), whereas the ratio of blood vessels and connective tissue to total nerve cross-sectional area was increased (p<0.05) in diabetic compared to control rats. In the retina, connective tissue growth factor (CTGF), transforming growth factor beta, type 2 receptor (TGFbeta-r2) mRNA and platelet-derived growth factor B (PDGF-B) mRNA were increased (p<0.035). Reduced ganglion cell function was correlated with increased CTGF and TGFbeta-r2, but not PDGF-B mRNA. In summary, the ganglion cell component exhibited the greatest level of dysfunction within the ERG components examined after 12 weeks of STZ-induced diabetes; the level correlated with increased CTGF and TGFbeta-r2 mRNA, but not with gross morphological changes in the retina or optic nerve.
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PMID:Investigating structural and biochemical correlates of ganglion cell dysfunction in streptozotocin-induced diabetic rats. 1945 Apr 51

Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes and one of the leading causes of death among patients with diabetes. DN is characterized by excessive amassing of extracellular matrix with thickening of glomerular and tubular basement membranes and increased amount of mesangial matrix, which ultimately progress to glomerulosclerosis and tubulo-interstitial fibrosis. The high intracellular glucose environment due to an increased cellular uptake of glucose activates several pathways related to the production of advanced glycation endproducts, cytokines, chemokines, growth factors, reactive oxidative species, which are all final mediators of renal damage in human and experimental diabetes. Several growth factors have been implicated in the pathogenesis of DN, through complex intra-renal systems. Transforming growth factor beta, connective tissue growth factor, vascular endothelial growth factor, growth hormone and insulin-like growth factors are among those best known and investigated. There are also data, even though limited, on the involvement of other two growth factors, epidermal growth factor and platelet derived growth factor, in the pathogenesis of DN. These growth factors, which are generally expressed in the normal kidney and whose levels increase in relation to diabetes, have been implicated in the control of renal matrix composition, cell hypertrophy, proliferation and survival, modulation of cells of the immune system, and enzymes involved in glucose metabolism. The development of specific inhibitors of growth factors has provided further evidence for the involvement of growth factors in the development and progression of DN and further studies might help in developing new potential therapeutical interventions.
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PMID:Role of growth factors in diabetic kidney disease. 1945 24


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