Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal disease is a common complication of diabetes mellitus. The pathogenesis of diabetic nephropathy is not well understood, but hyperglycemia seems to be a crucial factor. Recent evidence indicates that the overproduction of reactive oxygen species, observed in both clinical and experimental diabetes, and mitochondrial dysfunction are key factors in pathogenic process. The objective of this investigation was to test the hypothesis of whether hyperglycemia could affect kidney morphology and mitochondrial bioenergetics as well as susceptibility to oxidative stress in 12-month-old diabetic Goto-Kakizaki (GK) rats, a model of type 2 diabetes mellitus. We observed that there were no significant differences in the kidney respiratory function and phosphorylation capacity between GK and age-matched control Wistar rats. Mitochondria from kidneys of diabetic rats were equally susceptible to in vitro oxidative damage as those from normal rats, while coenzyme Q and alpha -tocopherol concentrations were similar in both types of preparations. However, the kidney of GK rats presented in most glomerulus a capillary basement membrane thickening with mesangial widening, in evolution to segmental glomerular sclerosis, and, in some interlobular arteries, excessive deposition of PAS-positive material at the tunica intima. The results show that the mild prolonged hyperglycemia and the kidney structural changes observed in GK rats are not sufficient to cause renal dysfunction and were not associated with functional and biochemical alterations in mitochondria.
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PMID:Mitochondrial function is not affected by renal morphological changes in diabetic goto-kakizaki rat. 2002 Oct 90

Heterocyclic indazole derivatives are claimed in patent WO2008138448 as inhibitors of the serum- and glucocorticoid-inducible-kinase 1 (SGK1) and drugs for the pharmacological treatment of SGK1-related diseases, such as diabetes, obesity, metabolic syndrome, systemic and pulmonary hypertension, cardiac fibrosis, hypertrophy and insufficiency, arteriosclerosis, glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, deranged electrolyte excretion, fibrosing and inflammatory disease (e.g., liver cirrhosis, lung fibrosis, rheumatism, arthrosis, Crohn s disease, chronic bronchitis, radiation fibrosis, sclerodermia, cystic fibrosis, scar formation and Alzheimer' disease), tumor growth, peptic ulcers and some disorders hitherto not conclusively shown to involve SGK1. Most of the claims are supported by the literature. SGK1 is ubiquitously expressed and its expression is stimulated by hyperglycemia, cell shrinkage, ischemia, glucocorticoids, mineralocorticoids and several inflammatory mediators including TGF-ss. SGK1 is activated by insulin and growth factors via the phosphatidylinositol-3-kinase pathway. SGK1 regulates ion channels (including ENaC, KCNE1/KCNQ1), carriers (including NCC, NHE3, SGLT1), Na(+)/K(+)-ATPase, enzymes (including glycogen-synthase-kinase-3) and transcription factors (including FOXO3a, ss-catenin, NF-kappaB). A gain-of-function SGK1 gene variant, carried by approximately 3 - 5% of Caucasians and approximately 10% of Africans, is associated with increased blood pressure, obesity and type 2 diabetes. In vitro and in vivo experiments suggested a critical role of SGK1 in renal fluid retention and hypertension, glucose-induced obesity, coagulation and increased matrix protein formation.
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PMID:Heterocyclic indazole derivatives as SGK1 inhibitors, WO2008138448. 2002 Dec 89

The combination of diabetes and renal failure is associated with accelerated cardiomyopathy, but the molecular mechanisms of how renal failure drives diabetic heart disease remain elusive. We speculated that the metabolic abnormalities of renal failure will affect the epigenetic control of cardiac gene transcription and sought to determine the histone H3 modification pattern in hearts of type 2 diabetic mice with several degrees of renal dysfunction. We studied the histone H3 modifications and gene expression in the heart of 6-month-old nondiabetic mice and type 2 diabetic db/db mice that underwent either sham surgery or uninephrectomy at 6 weeks of age, which accelerates glomerulosclerosis in db/db mice via glomerular hyperfiltration. Western blotting of hearts from uninephrectomized db/db mice with glomerulosclerosis, albuminuria, and reduced glomerular filtration rate revealed increased acetylation (K23 and 9), phosphorylation (Ser 10), dimethylation (K4), and reduced dimethylation of (K9) of cardiac histone H3 as compared with db/db mice with normal renal function or nondiabetic wild-type mice. This pattern suggests alterations in chromatin structure that favor gene transcription. In fact, hearts from uninephrectomized db/db mice revealed increased mRNA expression of multiple cardiomyopathy-related genes together with cardiomyocyte hypertrophy. These data suggest that renal failure alters cardiac histone H3 epigenetics, which foster cardiomyocyte hypertrophy in type 2 diabetes.
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PMID:Renal failure increases cardiac histone h3 acetylation, dimethylation, and phosphorylation and the induction of cardiomyopathy-related genes in type 2 diabetes. 2007 97

We recently showed that losartan and paricalcitol are synergistic in the treatment of diabetic nephropathy in a model of type 1 diabetes. To test this strategy in a model of type 2 diabetes, we treated 2-month-old diabetic Lprdb/db mice with losartan, paricalcitol, or a combination of losartan and paricalcitol for 3 months. Vehicle-treated diabetic mice developed progressive albuminuria and glomerular abnormalities with mesangial expansion and glomerulosclerosis compared to their non-diabetic littermate control mice. Accompanying damage of the glomerular filtration barrier was a marked reduction in podocyte number as well as reduced expression of slit diaphragm proteins. Further, there was increased glomerular expression of extracellular matrix proteins, monocyte chemoattractant protein-1 and transforming growth factor-beta. Losartan or paricalcitol each alone moderately ameliorated albuminuria and glomerular damage. However, their combined use showed a dramatic therapeutic synergism, manifested by prevention of progressive albuminuria, restoration of the glomerular filtration barrier, reversal of the decline in slit diaphragm proteins, reduced synthesis of extracellular matrix proteins, and reduction of glomerulosclerosis. These effects were accompanied by blockade of the compensatory increase of renin production and angiotensin I/II accumulation in the kidney. Thus, our study further shows that vitamin D analogs can increase the efficacy of AT1 receptor blockade, leading to a more effective prevention of kidney disease in type 2 diabetes.
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PMID:Combined vitamin D analog and AT1 receptor antagonist synergistically block the development of kidney disease in a model of type 2 diabetes. 2046 30

Obesity is fast becoming a bane for the present civilization, as a result of sedentary lifestyle, atherogenic diet, and a susceptible thrifty genotype. The concept of metabolic syndrome, which is a constellation of metabolic disturbances, has crystallized over the last 80 years with the aim of identifying those at greater risk of developing type 2 diabetes and cardiovascular disease. These patients have visceral obesity and insulin resistance characterized by hypertyriglyceridemia. Recently, it has been realized that they are also at an increased risk of chronic renal disease. Release of adipocytokines leads to endothelial dysfunction. There is also activation of systemic and local renin-angiotensin-aldosterone system, oxidative stress, and impaired fibrinolysis. This leads to glomerular hyperfiltration, proteinuria, focal segmental glomerulosclerosis (FSGS), and ultimately end-stage renal disease (ESRD). Treatment consists of lifestyle modifications along with optimal control of blood pressure, blood sugar and lipids. Metformin and thiazolidenidiones reduce insulin resistance; while angiotensin converting enzyme inhibitors and angiotensin receptor blockers reduce proteinuria and have a renoprotective effect. Exciting new medical therapies on the horizon include rimonabant a cannabinoid receptor type 1 antagonist, soy proteins, and peroxisome proliferator-activated receptor (PPAR) agonist. Bariatric surgery for morbid obesity has also been shown to be effective in treating metabolic syndrome.
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PMID:Metabolic syndrome and chronic kidney disease. 2036 11

Previous studies have demonstrated that prorenin plays a significant role in the development and progression of nephropathy in streptozotocin-induced diabetic animals, a model for type 1 diabetes, through a (pro)renin receptor-dependent mechanism. However, whether this novel mechanism also contributes to the mechanism of diabetic nephropathy in type 2 diabetes has remained undetermined. In 16-week-old db/db mice, a model for type 2 diabetes, we found a significant degree of glomerulosclerosis, enhanced immunostaining for the active site of renin (representing non-proteolytically activated prorenin), and an increased immunoreactivity to activated extracellular-signal-related protein kinase 1/2 in the kidneys. These changes were blocked by the chronic subcutaneous administration (1 mg/kg/day) of a decoy peptide with the "handle region" structure, which competitively inhibits prorenin binding to a "handle region"-specific binding protein, such as the (pro)renin receptor. The kidneys of db/db mice also contained increased angiotensin (Ang) I and II levels, eliciting significant microalbuminuria. Treatment with the "handle region" peptide significantly decreased the renal content of Ang I and II and inhibited the development of microalbuminuria. Thus prorenin also contributes to the development of nephropathy in type II diabetes, probably through a (pro)renin receptor-dependent mechanism.
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PMID:Involvement of receptor-bound prorenin in development of nephropathy in diabetic db/db mice. 2040 15

There remains a need for robust mouse models of diabetic nephropathy (DN) that mimic key features of advanced human DN. The recently developed mouse strain BTBR with the ob/ob leptin-deficiency mutation develops severe type 2 diabetes, hypercholesterolemia, elevated triglycerides, and insulin resistance, but the renal phenotype has not been characterized. Here, we show that these obese, diabetic mice rapidly develop morphologic renal lesions characteristic of both early and advanced human DN. BTBR ob/ob mice developed progressive proteinuria beginning at 4 weeks. Glomerular hypertrophy and accumulation of mesangial matrix, characteristic of early DN, were present by 8 weeks, and glomerular lesions similar to those of advanced human DN were present by 20 weeks. By 22 weeks, we observed an approximately 20% increase in basement membrane thickness and a >50% increase in mesangial matrix. Diffuse mesangial sclerosis (focally approaching nodular glomerulosclerosis), focal arteriolar hyalinosis, mesangiolysis, and focal mild interstitial fibrosis were present. Loss of podocytes was present early and persisted. In summary, BTBR ob/ob mice develop a constellation of abnormalities that closely resemble advanced human DN more rapidly than most other murine models, making this strain particularly attractive for testing therapeutic interventions.
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PMID:BTBR Ob/Ob mutant mice model progressive diabetic nephropathy. 2070 6

The renin-angiotensin system plays a central role in the pathological mechanisms of diabetic nephropathy and is regulated by renal expression of cyclooxygenase-2 (COX-2). In the present study, the kidneys of diabetic KK-A(y) mice, a model of human type 2 diabetes, were investigated histologically and immunohistochemically at 8, 12, 16, and 20 weeks of age, and changes in renal lesions and expression of COX-2 and renin were evaluated quantitatively. Glomerular damage, characterized by expansion of mesangial matrices and nodular lesions, was observed in the kidneys of these mice. The glomerular sclerosis score gradually increased with age and was significantly higher than those of age-matched control C57BL/6 mice at 12, 16, and 20 weeks of age. Although mild tubulointerstitial damage was observed, there was no significant change in the interstitial fibrosis score. These findings were considered early diabetic nephropathy changes. COX-2-positive signals were consistently detected in the macula densa cells of the thick ascending limbs in all KK-A(y) mice, with a slightly higher score observed at 8 weeks of age. No COX-2-positive signals were detected in C57BL/6 mice. Renin-positive signals were commonly detected in the juxtaglomerular arterioles, and the scores in KK-A(y) mice increased at 16 weeks and decreased at 20 weeks of age. The present study demonstrated activation of renal COX-2 and renin expression in diabetic KK-A(y) mice at different stages. This finding suggests that these two enzymes contribute to the development and progression of diabetic nephropathy via different mechanisms.
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PMID:Immunohistochemical examination of cyclooxygenase-2 and renin in a KK-A(y) mouse model of diabetic nephropathy. 2066 Sep 94

Familial clustering of disparate kidney diseases including clinically diagnosed hypertensive and diabetic nephropathy, idiopathic focal segmental glomerulosclerosis, and HIV-associated nephropathy are often observed in African Americans. Admixture mapping recently identified the nonmuscle myosin heavy chain 9 gene (MYH9) as a susceptibility factor strongly associated with several nondiabetic etiologies of end-stage renal disease in African Americans, less strongly with diabetes-associated end-stage renal disease. MYH9-associated nephropathies reside in the spectrum of focal segmental glomerulosclerosis/focal global glomerulosclerosis. The renal histology in proteinuric African Americans homozygous for MYH9 risk variants with longstanding type 2 diabetes mellitus is unknown. We report a case of coincident idiopathic focal segmental glomerulosclerosis collapsing variant and diabetic nephropathy in an African American homozygous for the MYH9 E1 risk haplotype. This case demonstrates that diabetic African Americans with overt proteinuria can have mixed renal lesions, including those in the spectrum of MYH9-associated nephropathy. Careful interpretation of kidney biopsies in proteinuric African Americans with diabetes is necessary to exclude coincident nondiabetic forms of nephropathy, precisely define etiologies of kidney disease, and determine the natural history and treatment response in mixed lesions of diabetes-associated and MYH9-associated kidney disease.
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PMID:Coincident idiopathic focal segmental glomerulosclerosis collapsing variant and diabetic nephropathy in an African American homozygous for MYH9 risk variants. 2107 26

The progression of diabetic nephropathy is associated with an infiltration of macrophages expressing different phenotypes. As classically activated chemokine receptor CCR2+ macrophages are thought to drive tissue inflammation and remodeling, we tested whether blocking CCR2 could reduce intrarenal inflammation and prevent glomerulosclerosis in type 2 diabetes. This was achieved with RO5234444, an orally active small-molecule CCR2 antagonist that blocks ligand binding, its internalization, and monocyte chemotaxis. Male type 2 diabetic db/db mice were uninephrectomized to increase glomerular hyperfiltration to accelerate the development of glomerulosclerosis. From 16 weeks until killing at 24 weeks of age, mice were chow fed with or without admixed antagonist to achieve a trough plasma concentration above IC50 for binding in the mouse. CCR2 blockade reduced circulating monocyte levels, but did not affect total leukocyte or neutrophil numbers, and was associated with a reduction in the number of macrophages and apoptotic podocytes in the glomerulus. This treatment resulted in a higher total number of podocytes, less glomerulosclerosis, reduced albuminuria, and a significantly improved glomerular filtration rate. This successful pre-clinical trial suggests that this antagonist may now be ready for testing in humans with the nephropathy of diabetes mellitus.
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PMID:An orally active chemokine receptor CCR2 antagonist prevents glomerulosclerosis and renal failure in type 2 diabetes. 2150 25


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