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)

Although hemodynamic and metabolic factors are individually implicated in the development of diabetic nephropathy, their interaction has not been defined clearly. In this study, the effects of angiotensin II (Ang II) and advanced glycation end products (AGE) both individually on each other are explored and compared. In the first study arm, Sprague-Dawley rats received a continuous infusion of AGE-modified rat serum albumin (RSA) or unmodified RSA for 4 wk with or without the angiotensin receptor type 1 antagonist valsartan. In the second arm, animals received a continuous infusion of Ang II (58.3 ng/kg per min) with or without the AGE inhibitor pyridoxamine. Components of the intrarenal renin-angiotensin system were measured using real time reverse transcription-PCR, immunohistochemistry, and standard angiotensin-converting enzyme (ACE) activity assays. Renal and serum AGE were quantified by immunohistochemistry, ELISA, and AGE-fluorescence. After an infusion of AGE-RSA, renal expression of angiotensinogen, ACE, renin, and angiotensin receptor type 1 were increased significantly (all P < 0.01), and ACE activity was elevated. This was associated with tubular and glomerular hypertrophy and AGE accumulation, which could be antagonized by valsartan. However, valsartan had no effect on increased filtration fraction associated with an AGE-RSA infusion. At the same time, an infusion of Ang II increased the serum and renal accumulation of AGE and advanced oxidation protein products and induced renal hypertrophy and salt retention that could be antagonized by pyridoxamine. However, pyridoxamine had no effect on renal vasoconstriction manifested by reduced renal blood flow. AGE and Ang II have overlapping activities in the kidney. The beneficial effects of blockade of either pathway underline the importance of this interaction in diabetic renal disease and the aging kidney.
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PMID:Interactions between renin angiotensin system and advanced glycation in the kidney. 1610 77

The aim of this study was to clarify the role of the renal renin-angiotensin system (RAS) in diabetic nephropathy (DN), which was induced by injection of streptozotocin (STZ). Male CBA/N and CBA/J mice were compared in this study. The former possesses a single renin gene, Ren1, whereas the latter carries two renin genes, Ren1 and Ren2. To examine the molecular dynamics of renal RAS, including renin, angiotensinogen (Agt), angiotensin-converting enzyme (Ace), angiotensin type 1 (Agtr1) and type 2 (Agtr2) receptors in experimental DN, we performed laser-microdissection (LMD) followed by reverse transcriptase nested polymerase chain reaction using each specific primer pairs and immunohistochemistry for renin and angiotensin II. CBA/N mice had a higher response after injection of STZ than CBA/J mice, showing a significant increase of the kidney/body weight ratio, although there was no significant difference between the two strains for the blood glucose level or pancreatic beta-cell response. The onset of renal pathological changes associated with DN was earlier and more severe in CBA/N mice than in CBA/J mice. Distinct immunoreactivities for renin and angiotensin II were newly distributed on the flattened epithelial cells in the dilated distal tubules in the cortex as well as the collecting ducts in the cortex and medulla, and were demonstrated more intensely in CBA/N mice than in CBA/J mice. Microdissectional analysis in both DN models revealed a higher incidence of RAS-related gene expression in CBA/J, Ren 1 Ren 2 mice than in CBA/N, Ren 1 mice. These findings suggest that intrarenal RAS plays an important role in the onset of renal pathological changes associated with DN. Additionally, Ren 1 mice have more severe histopathological nephropathy than Ren1 Ren2 mice, followed by marked production of angiotensin II.
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PMID:Upregulation of renal renin-angiotensin system in mouse diabetic nephropathy. 1619 Mar 18

Recent findings related to the renin-angiotensin system have provided a more elaborated understanding of the pathophysiology of hypertension and kidney diseases. These findings have led to unique concepts and issues regarding the intrarenal renin-angiotensin system. Angiotensinogen is the only known substrate for renin that is the rate-limiting enzyme of the renin-angiotensin system. Because the level of angiotensinogen in human beings is close to the Michaelis-Menten constant value for renin, changes in angiotensinogen levels can control the activity of the renin-angiotensin system, and its upregulation may lead to elevated angiotensin peptide levels and increases in blood pressure. Enhanced intrarenal angiotensinogen mRNA or protein levels or both have been observed in multiple models of hypertension including angiotensin II-dependent hypertensive rats, Dahl salt-sensitive hypertensive rats, and spontaneously hypertensive rats, as well as in kidney diseases including diabetic nephropathy, immunoglobulin A (IgA) nephropathy, and radiation nephropathy. Renal angiotensinogen is formed primarily in proximal tubular cells and is secreted into the tubular fluid. Urinary angiotensinogen excretion rates show a clear relationship to kidney angiotensin II contents and kidney angiotensinogen levels, suggesting that urinary angiotensinogen may serve as an index of the intrarenal renin-angiotensin system status. Establishment of concise and accurate methods to measure human angiotensinogen may allow clinical studies that would provide important information regarding the roles of intrarenal angiotensinogen in the development and progression of hypertension and kidney diseases.
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PMID:Young Scholars Award Lecture: Intratubular angiotensinogen in hypertension and kidney diseases. 1664 30

Excess body weight may be associated with various functional/structural lesions of the kidney. The spectrum ranges from glomerulomegaly with or without focal or segmental glomerulosclerosis, to diabetic nephropathy, to carcinoma of the kidney and nephrolithiasis. The first sign of renal injury is microalbuminuria or frank proteinuria, in particular in the presence of hypertension. The occurrence of microalbuminuria and/or chronic kidney insufficiency (glomerular filtration rate < 60 mL/min/1.73 m2) is related to the increasing number of components of the metabolic syndrome, ie, central obesity, elevated fasting blood glucose level, hypertriglycerides, low high-density lipoprotein cholesterol, and hypertension. In the long run, end-stage renal failure may develop. An increased body mass index is particularly harmful in patients with reduced renal functional mass (unilateral renal agenesis or nephrectomy) and other renal diseases (immunoglobulin A nephritis and chronic graft dysfunction after kidney transplantation). In the pathogenesis of obesity-associated glomerulopathy, hyperfiltration is of fundamental importance. The factors involved are energy intake (high protein and salt), hyperinsulinemia, and enhanced tubuloglomerular feedback because of increased sodium reabsorption. The adrenergic and renin-angiotensin-aldosterone systems as well as glucocorticoids are stimulated. In addition, several active proteins generated in the central adipose tissue, such as leptin, proinflammatory cytokines, plasminogen activator inhibitor-1, angiotensinogen, and growth factors (transforming growth factor-beta1), as well as low levels of the protective adiponectin, may contribute to renal injury. Of greatest importance is the development of hypertension and of diabetes, which are directly related to the severity of central obesity. Obesity-associated renal disease should be prevented or retarded by weight reduction following lifestyle modification (salt restriction, hypocaloric diet, aerobic exercise), or eventually by antiobesity medication or bariatric surgery. In the presence of glomerulopathy and/or hypertension, angiotensin converting enzyme inhibitors or angiotensin II type I receptor blockers are the drugs of choice to improve glomerular hyperfiltration.
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PMID:Renal disease in obesity: the need for greater attention. 1682 23

To elucidate the role of the renin-angiotensin system (RAS) in diabetic nephropathy, we examined the association between diabetic nephropathy in a large cohort of Japanese type 2 diabetic patients and polymorphisms within the genes that encode angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II receptor type 1 (AGTR1). Single nucleotide polymorphisms (SNPs) within these genes were genotyped using invader assay in 747 nephropathy cases and 557 control subjects. Eight SNPs within the ACE gene were significantly associated with diabetic nephropathy (P<0.05), including five SNPs in almost complete linkage disequilibrium to the insertion/deletion polymorphism in the 16th intron (P=0.01, odds ratio =1.34, 95% CI 1.07-1.69). Three SNPs within the AGT, including M235T and one SNP in the AGTR1, were also significantly associated with nephropathy (M235T P=0.01, odds ratio =0.74, 95% CI 0.59-0.94). In addition, we found that the allelic mRNA expression corresponding to the 235M allele was significantly higher than that for the 235T allele in normal kidney tissues. Furthermore, we found a significant additional effect of these three genes by a step-wise logistic regression analysis (final empirical P value =0.00005). We concluded that RAS gene polymorphisms may contribute to the susceptibility to diabetic nephropathy in type 2 diabetes.
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PMID:Combinational effect of genes for the renin-angiotensin system in conferring susceptibility to diabetic nephropathy. 1714 91

Increased generation of reactive oxygen species (ROS) leads to oxidative stress in diabetes. Catalase is a highly conserved heme-containing protein that reduces hydrogen peroxide to water and oxygen and is an important factor decreasing cellular injury owing to oxidative stress. Hyperglycemic conditions increase oxidative stress and angiotensinogen gene expression. Angiotensinogen conversion to angiotensin II leads to a furtherance in oxidative stress through increased generation of reactive oxygen species. In this study, we utilized mice transgenically overexpressing rat catalase in a kidney-specific manner to determine the impact on ROS, angiotensinogen and apoptotic gene expression in proximal tubule cells of diabetic animals. Proximal tubules isolated from wild-type and transgenic animals without or with streptozotocin-induced diabetes were incubated in low glucose media in the absence or presence of angiotensin II or in a high-glucose media. Our results show that the overexpression of catalase prevents the stimulation of ROS and angiotensinogen mRNA in tubules owing to elevated glucose or angiotensin II in vitro. Additionally, overexpression of catalase attenuated ROS generation, angiotensinogen and proapoptotic gene expression and apoptosis in the kidneys of diabetic mice in vivo. Our studies point to an important role of ROS in the pathophysiology of diabetic nephropathy.
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PMID:Catalase overexpression attenuates angiotensinogen expression and apoptosis in diabetic mice. 1755 51

Hypertension is caused by metabolic syndrome. The primary cause of hypertension, however, is excess salt intake and an impaired renal salt excretory mechanism of the tubuloglomerular feedback mechanism involved in macula densa. Salt-losing nephropathy such as Gitelman's syndrome (which is caused by loss of function mutation in the tyhiazide-sensitive Na-Cl transporter, NCCT gene) is lacking in hypertension and has fewer cardiovascular complications despite the presence of the stimulated rennin-angiotensin-aldosterone system. It has been reported that an NCCT gene mutation is closely associated with diabetic nephropathy, suggesting an important role of NaCl metabolism in diabetic nephropathy. Loss of function of peroxisome proliferator-activated receptor(PPAR) -gamma(one of the key molecules of insulin resistance) has been shown to lead to obesity, diabetes and hypertension, suggesting a common basic background of such diseases. High insulin levels observed in insulin resistance would stimulate salt reabsorption in renal tubules, which may result in high blood pressure. Adipocytokines such as adiponectin, leptin and angiotensinogen may play some roles in metabolic syndrome. Taken together, good understanding of salt intake and its related factors in renal salt metabolism involved in metabolic syndrome will suppress further progression of atherosclerotic changes including chronic kidney disease.
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PMID:[Hypertension and metabolic syndrome/lifestyle diseases]. 1759 91

Genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy and type II diabetes. To identify the genetic polymorphisms associated with diabetic nephropathy and type II diabetes, we performed a genome-wide association study using single-nucleotide polymorphisms as genetic markers. We also analyzed polymorphisms within the genes encoding for the renin-angiotensin system that were considered as candidate genes for diabetic nephropathy susceptibility and the transcription factor 7-like 2 (TCF7L2) as a candidate for type II diabetes, in a large cohort of a Japanese population. A genome-wide association study identified SLC12A3 and engulfment and cell motility 1 gene as the new candidates for diabetic nephropathy and transcription factor-activating protein 2beta as a novel susceptibility gene for type II diabetes; this observation was based on the significant association between the polymorphisms within the genes and the corresponding diseases (P<0.0001). Further, we discovered that the genes encoding the angiotensin-converting enzyme, angiotensinogen, and angiotensin II type I receptor have a significant combinational effect on conferring susceptibility to diabetic nephropathy. Furthermore, TCF7L2 that has been reported as a convincing susceptibility gene for type II diabetes in Caucasian populations was also shown to be associated with type II diabetes in a Japanese population. These genes could be considered as strong susceptibility genes for diabetic nephropathy and type II diabetes in the Japanese, although the new candidates that have been identified by genome-wide screening need to be examined in greater detail by several replication studies.
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PMID:Genetic variations associated with diabetic nephropathy and type II diabetes in a Japanese population. 1765 10

1,25-Dihydroxyvitamin D3 negatively regulates the renin-angiotensin system (RAS), which plays a critical role in the development of diabetic nephropathy. We tested if mice lacking the vitamin D receptor (VDR) are more susceptible to hyperglycemia-induced renal injury. Diabetic VDR knockout mice developed more severe albuminuria and glomerulosclerosis due to increased glomerular basement membrane thickening and podocyte effacement. More fibronectin (FN) and less nephrin were expressed in the VDR knockout mice compared to diabetic wild-type mice. In receptor knockout mice, increased renin, angiotensinogen, transforming growth factor-beta (TGF-beta), and connective tissue growth factor accompanied the more severe renal injury. 1,25-Dihydroxyvitmain D3 inhibited high glucose (HG)-induced FN production in cultured mesangial cells and increased nephrin expression in cultured podocytes. 1,25-Dihydroxyvitmain D3 also suppressed HG-induced activation of the RAS and TGF-beta in mesangial and juxtaglomerular cells. Our study suggests that receptor-mediated vitamin D actions are renoprotective in diabetic nephropathy.
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PMID:Renoprotective role of the vitamin D receptor in diabetic nephropathy. 1816 10

The intrarenal renin-angiotensin system (RAS) plays an important role in the progression of diabetic nephropathy. We have previously reported that mice overexpressing angiotensinogen in renal proximal tubular cells (RPTC) develop hypertension, albuminuria, and renal injury. Here, we investigated whether activation of the intrarenal RAS contributes to apoptosis of RPTC in diabetes. Induction of diabetes with streptozotocin in these transgenic mice led to significant increases in BP, albuminuria, RPTC apoptosis, and proapoptotic gene expression compared with diabetic nontransgenic littermates. Insulin and/or RAS blockers markedly attenuated these changes. Hydralazine prevented hypertension but not albuminuria, RPTC apoptosis, or proapoptotic gene expression. In vitro, high-glucose medium significantly increased apoptosis and caspase-3 activity in rat immortalized RPTC overexpressing angiotensinogen compared with control cells, and these changes were prevented by insulin and/or RAS blockers. In conclusion, intrarenal RAS activation and high glucose may act in concert to increase tubular apoptosis in diabetes, independent of systemic hypertension.
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PMID:Overexpression of angiotensinogen increases tubular apoptosis in diabetes. 1805 17


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