UMLS:C0011881 - FACTA Search

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Query: UMLS:C0011881 (diabetic nephropathy)
10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with glycogen storage disease type Ia (GSD-Ia) develop renal disease of unknown etiology despite intensive dietary therapies. This renal disease shares many clinical and pathological similarities to diabetic nephropathy. We studied the expression of angiotensinogen, angiotensin type 1 receptor, transforming growth factor-beta1, and connective tissue growth factor in mice with GSD-Ia and found them to be elevated compared to controls. While increased renal expression of angiotensinogen was evident in 2-week-old mice with GSD-Ia, the renal expression of transforming growth factor-beta and connective tissue growth factor did not increase for another week; consistent with upregulation of these factors by angiotensin II. The expression of fibronectin and collagens I, III, and IV was also elevated in the kidneys of mice with GSD-Ia, compared to controls. Renal fibrosis was characterized by a marked increase in the synthesis and deposition of extracellular matrix proteins in the renal cortex and histological abnormalities including tubular basement membrane thickening, tubular atrophy, tubular dilation, and multifocal interstitial fibrosis. Our results suggest that activation of the angiotensin system has an important role in the pathophysiology of renal disease in patients with GSD-Ia.
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PMID:Angiotensin mediates renal fibrosis in the nephropathy of glycogen storage disease type Ia. 1807 99

1. The present study was performed to test the hypothesis that the reactive oxygen species (ROS)-angiotensinogen (AGT)-renin angiotensin system (RAS) axis is sequentially activated in the development of diabetic nephropathy in Zucker diabetic fatty (ZDF) obese rats. 2. Genetic pairs of male ZDF obese and control ZDF lean rats (n = 12 of each species) were killed every 3 weeks from 12 to 21 weeks of age (n = 6 at each time point). 3. The ZDF obese rats developed diabetes mellitus at 12 weeks. At that time, urinary excretion rates of 8-isoprostane were similar between the groups; however, urinary 8-isoprostane levels were significantly increased at 15 weeks in ZDF obese rats compared with controls (36 +/- 6 vs 15 +/- 2 ng/day, respectively). At 15 weeks, protein levels of cortical angiotensinogen were similar between groups; however, cortical angiotensinogen levels were significantly increased at 18 weeks in ZDF obese rats compared with controls (relative ratio of 2.32 +/- 0.21 vs 1.00 +/- 0.20, respectively). At 12 weeks, angiotensin (Ang) II-like immunoreactivity was similar between groups in both the glomeruli and tubules; however, AngII-like immunoreactivity was increased significantly at 21 weeks in ZDF obese rats compared with controls (relative ratios of 1.98 +/- 0.55 vs 1.00 +/- 0.03, respectively, for glomeruli and 1.58 +/- 0.16 vs 1.00 +/- 0.13, respectively, for tubules). Moreover, at 21 weeks, the desmin-positive area in the glomeruli (0.63 +/- 0.08 vs 0.22 +/- 0.05%) and Masson's trichrome stain-positive area in the interstitium (4.97 +/- 0.05 vs 3.18 +/- 0.41%) were significantly increased in ZDF obese rats compared with controls, even though these differences had not been observed earlier. 4. These data suggest that the sequential activation of the ROS-AGT-RAS axis plays an important role in the development of diabetic nephropathy in ZDF obese rats.
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PMID:Sequential activation of the reactive oxygen species/angiotensinogen/renin-angiotensin system axis in renal injury of type 2 diabetic rats. 1843 60

Genetic predisposition has been proposed to be a major determinant in the development of renal complications of diabetes. Among candidate genes examined for susceptibility to diabetic nephropathy, angiotensin-converting enzyme (ACE) gene has been found to be associated with pathogenesis and progression of diabetic nephropathy. However, the role of other renin-angiotensin system (RAS) polymorphisms and their possible interactions with different ACE I/D genotypes are less clearly defined. Recent studies also show that ACE haplotypes may be better predictors to disease susceptibility. Thus, in the present study, we evaluated the association of ACE haplotypes and the interactions of ACE, angiotensinogen (AGT), and angiotensin II receptor type I (AGTR1) gene polymorphisms with DNP in Asian Indians. We genotyped seven variants of the RAS pathway genes (ACE, AGT, and AGTR1) in type 2 diabetic cohorts without nephropathy (DM) and with nephropathy (DNP), using allele-specific oligonucleotide-PCR, and PCR-restriction fragment length polymorphism assays. We studied the interaction of these variants with each other and ACE I/D polymorphism. Frequency of ACE D allele and DD genotype (ACE I/D) was significantly higher in DNP (p < 0.005) and was associated with increased risk of nephropathy. The frequency of T allele, MT/TT genotypes (AGT: M235T), and C allele 1166CC genotype (AGTR1: A1166C) was higher and associated with increased risk of DNP (235T, p < 0.0001; 235TT/MT, p < 0.01; 1166C, p < 0.007; 1166CC, p < 0.0001). The ACE locus revealed a near doubling in the prevalence of T-D-G risk haplotype (odds ratio, 1.76) in DNP (0.13) compared to DM (0.08; p < 0.02). ACE haplotypes carrying the I allele were associated with a lower risk of DNP (C-I-A, p < 0.04; C-I-G, p < 0.008). ACE ID/DD genotypes in combination with ACE rs4311, rs4343, and AGT rs699 mutant genotypes increased the risk of DNP development fourfold (p < 0.01). This study provides the first evidence for a disease haplotype for DNP at the ACE locus in Asian Indians. The study further indicates that ACE D allele individually and in interaction with other RAS single-nucleotide polymorphisms significantly increases the risk of nephropathy in type 2 diabetic patients of Asian Indian origin.
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PMID:ACE variants interact with the RAS pathway to confer risk and protection against type 2 diabetic nephropathy. 1910 84

The renin-angiotensin system (RAS) is a major mediator of renal injury in diabetic nephropathy. Our previous studies demonstrated that 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] plays a renoprotective role by suppressing the RAS, with renin and angiotensinogen (AGT) as the main targets. The mechanism whereby 1,25(OH)(2)D(3) transcriptionally suppresses renin gene expression has been elucidated; however, how vitamin D regulates AGT remains unknown. Exposure of mesangial cells or podocytes to high glucose (HG; 30 mM) markedly stimulated AGT expression. In mesangial cells, the stimulation was inhibited by 1,25(OH)(2)D(3) (20 nM) or NF-kappaB inhibitor BAY 11-7082, suggesting the involvement of NF- kappaB in HG-induced AGT expression and the interaction between 1,25(OH)(2)D(3) and NF-kappaB in the regulation. Plasmid pNF-kappaB-Luc luciferase reporter assays showed that 1,25(OH)(2)D(3) blocked HG-induced NF-kappaB activity. EMSA and ChIP assays demonstrated increased p65/p50 binding to a NF-kappaB binding site at -1734 in the AGT gene promoter upon high glucose stimulation, and the binding was disrupted by 1,25(OH)(2)D(3) treatment. Overexpression of p65/p50 overcame 1,25(OH)(2)D(3) suppression, and mutation of this NF-kappaB binding site blunted 1,25(OH)(2)D(3) suppression of the promoter activity. In mice lacking the vitamin D receptor, AGT mRNA expression in the kidney was markedly increased compared with wild-type mice, and AGT induction in diabetic mice was suppressed by treatment with a vitamin D analog. These data indicate that 1,25(OH)(2)D(3) suppresses hyperglycemia-induced AGT expression by blocking NF-kappaB-mediated pathway.
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PMID:1,25-Dihydroxyvitamin D3 suppresses high glucose-induced angiotensinogen expression in kidney cells by blocking the NF-{kappa}B pathway. 1919 28

The intrarenal renin-angiotensin system (RAS) plays a key role in the development of diabetic nephropathy. Recently, we showed that combination therapy with an AT(1) receptor blocker (ARB) and an activated vitamin D analog produced excellent synergistic effects against diabetic nephropathy, as a result of blockade of the ARB-induced compensatory renin increase. Given the diversity of vitamin D analogs, here we used a pro-drug vitamin D analog, doxercalciferol (1alpha-hydroxyvitamin D(2)), to further test the efficacy of the combination strategy in long-term treatment. Streptozotocin-induced diabetic DBA/2J mice were treated with vehicle, losartan, doxercalciferol (0.4 and 0.6 microg/kg), or losartan and doxercalciferol combinations for 20 wk. Vehicle-treated diabetic mice developed progressive albuminuria and glomerulosclerosis. Losartan alone moderately ameliorated kidney injury, with renin being drastically upregulated. A similar therapeutic effect was seen with doxercalciferol alone, which markedly suppressed renin and angiotensinogen expression. The losartan and doxercalciferol combination most effectively prevented albuminuria, restored glomerular filtration barrier structure, and dramatically reduced glomerulosclerosis in a dose-dependent manner. These effects were accompanied by blockade of intrarenal renin upregulation and ANG II accumulation. These data demonstrate an excellent therapeutic potential for doxercalciferol in diabetic renal disease and confirm the concept that blockade of the compensatory renin increase enhances the efficacy of RAS inhibition and produces synergistic therapeutic effects in combination therapy.
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PMID:Long-term therapeutic effect of vitamin D analog doxercalciferol on diabetic nephropathy: strong synergism with AT1 receptor antagonist. 1953 71

Diabetic nephropathy is associated with mesangial ECM (extracellular matrix) accumulation. We have shown that AT-1R [Ang II (angiotensin II) type I receptor] signalling induces ECM proteins via transactivation of PI3K (phosphoinositide 3-kinase) in mesangial cells. In the present study, we examined the mechanisms underlying the effect of high ambient glucose on cell proliferation and ECM expansion in a mesangial context. High glucose induced increases in PI3K activity, proliferation and ECM accumulation in mesangial cells. These effects were abrogated by losartan, an AT-1R antagonist, but not by [Sar1,Thr8]-Ang II (Sar is sarcosine), an inactive analogue of Ang II, or by a neutralizing antibody against Ang I/II. Overexpression of a constitutively active PI3Kalpha or AT-1R alone was sufficient to induce similar changes by high glucose. In contrast, overexpression of an inactive AT-1R lowered the basal levels and rendered the cells non-responsive to high glucose. Moreover, cells overexpressing wild-type AT-1R had enhanced sensitivity to acute Ang II stimulation. These cells, however, did not respond to conditioned medium obtained from mesangial cells cultured in high glucose. We further demonstrated that iAng (intracellular Ang II) can be induced by high glucose but only under certain conditions. Efficient suppression of iAng by short hairpin RNA against angiotensinogen, however, did not affect high glucose-induced effects on MES-13 cells. These results suggest that high ambient glucose induces activation of AT-1R in an Ang II-independent manner to transactivate PI3K, resulting in proliferation and ECM accumulation in mesangial cells.
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PMID:High ambient glucose induces angiotensin-independent AT-1 receptor activation, leading to increases in proliferation and extracellular matrix accumulation in MES-13 mesangial cells. 1960 48

Recent knowledge demonstrated that the renin-angiotensin system (RAS) functions as a local renal paracrine system. All components of the RAS are present within the kidney and include angiotensinogen, renin, angiotensin I, angiotensin-converting enzymes, angiotensin II, the angiotensin II type 1 (AT(1)) receptor and the angiotensin II type 2 (AT(2)) receptor. Angiotensin II is the major effector hormone of the RAS and contributes to a variety of renal and cardiovascular physiologic and pathologic mechanisms through stimulation of AT(1) and AT(2) receptors. Angiotensin receptor blockers were developed based on the advanced knowledge of the AT(1) receptor contribution to development of a variety of kidney, vascular and cardiac diseases including but not limited to hypertension, diabetic nephropathy, heart failure, myocardial infarction and atherosclerosis. In contrast, knowledge concerning the role of the AT(2) receptor in health and disease is still emerging. The AT(2) receptor is believed to counterbalance the effects of the AT(1) receptor through influencing cellular differentiation, vasodilation, inhibition of cellular proliferation and hypertrophy, nitric oxide production and natriuresis. Thus, the pursuit of a specific AT(2) receptor agonist is a potentially fruitful area for combating renal and cardiovascular diseases. This review focuses on the role of the AT(2) receptor in the kidney.
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PMID:The angiotensin II type 2 receptor and the kidney. 1986 47

Treatment with autologous bone marrow transplantation (ABMT) can change the natural history of diabetes in patients with new-onset Type 1 diabetes (T1D). Effects of syngeneic bone marrow transplantation (syn-BMT) on diabetic nephropathy were studied in streptozotocin-induced diabetic mice. Diabetic mice received sibling's bone marrow on days 3, 10, 20, or 40 after T1D onset, respectively. Renal pathology, levels of oxidative stress, and the expressions of angiotensinogen (AGT), monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor beta 1 (Tgf-beta1) mRNA were investigated. Treatment with syn-BMT when disease was early-onset reduced mesangial area expansion and kidney enlargement; besides, if it is given on day 10, syn-BMT attenuated glomerular hypertrophy. Oxidative stress factors such as catalase (CAT) and superoxide radical anion O(2-) (O(2-)) were markedly maintained by syn-BMT compared to mice without treatment. In diabetic mice without treatment, renal AGT and MCP-1 mRNA were increased, while they were effectively suppressed by syn-BMT. But it showed no changes or even increment in Tgf-beta1 mRNA after syn-BMT. Syn-BMT, if applied when disease was early-onset, ameliorated diabetic renal injury. These preventive effects could be partly via maintaining oxidative stress and expression of AGT and MCP-1 in kidney in streptozotocin-diabetic mice.
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PMID:Preventive effects of syngeneic bone marrow transplantation on diabetic nephropathy in mice. 2004 60

In 2002, Nguyen et al. cloned the (pro)renin receptor ((P)RR). Two years later, Suzuki, Ichihara and colleagues provided a concept to inhibit the (P)RR through HRP. This decapeptide mimics a sequence of the prorenin prosegment and functions thereby as a decoy peptide. They showed that HRP prevented diabetic nephropathy in rodents and ameliorated renal and cardiac damage in spontaneously hypertensive rats. We tested HRP and the human renin inhibitor aliskiren in transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR). Only aliskiren, but not HRP, was able to ameliorate target organ damage in this model. HRP had also no effect on target organ damage in renovascular hypertensive rats. In vitro studies showed that HRP did not inhibit (pro)renin binding and signaling. More confusing was the fact that HRP bound to cells lacking (P)RR on their surface. We believe that HRP does not act as a competitive antagonist for the (P)RR and promotes its action via an alternative mechanism. Elucidating this mechanism could offer further opportunities, in terms of (pro)renin research.
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PMID:The (pro)renin receptor and the mystic HRP--is there a role in cardiovascular disease? 2051 98

1. Renal tubular epithelial cells can undergo epithelial to mesenchymal transition (EMT) under hyperglycaemic conditions, which is associated with renal interstitial fibrosis. Activation of the renin-angiotensin system (RAS) is involved in diabetic nephropathy. The present study investigated the positive role of angiotensin AT1 receptors in high glucose-induced EMT in cultured tubular epithelial cells. 2. A rat kidney proximal tubular epithelial cell line (NRK-52E) was used in the present study. Levels of EMT makers, namely E-cadherin and vimentin, were estimated using fluorescence immunocytochemistry, mRNA levels of angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and AT1 receptors were determined by real-time polymerase chain reaction, protein levels of E-cadherin, vimentin, fibronectin, matrix metallopeptidase (MMP)-9 and phosphorylated extracellular signal-regulated kinase (ERK) 1/2 were analysed by western blotting and the concentrations of angiotensin (Ang) II and transforming growth factor (TGF)-beta1 in the culture medium were determined by enzyme immunoassay and ELISA. 3. High glucose (30 mmol/L) induced EMT and increased the synthesis of fibronectin and MMP-9. Furthermore, high glucose increased AGT, ACE and AT(1) receptor mRNA levels, as well as AngII and TGF-beta1 concentrations in the culture medium and ERK1/2 phosphorylation. Pretreatment of cells for 15 min with the AT1 receptor antagonist losartan (10(-5) mol/L) attenuated high glucose-induced increases in TGF-beta1 and ERK1/2 phosphorylation and reduced EMT, as well as the consequent synthesis of fibronectin and MMP-9. 4. The results of the present study suggest that the activated local RAS mediates high glucose-induced EMT. By activating AT1 receptors and stimulating TGF-beta1 synthesis, the elevated local RAS participates in high glucose-induced EMT and increased extracellular matrix secretion.
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PMID:Angiotensin AT1 receptor activation mediates high glucose-induced epithelial-mesenchymal transition in renal proximal tubular cells. 2059 Jun 68

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