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 most cellular glutathione (GSH) is in the cytoplasm, a distinctly regulated pool is present in mitochondria. Inasmuch as GSH synthesis is primarily restricted to the cytoplasm, the mitochondrial pool must derive from transport of cytoplasmic GSH across the mitochondrial inner membrane. Early studies in liver mitochondria primarily focused on the relationship between GSH status and membrane permeability and energetics. Because GSH is an anion at physiological pH, this suggested that some of the organic anion carriers present in the inner membrane could function in GSH transport. Indeed, studies by Lash and colleagues in isolated mitochondria from rat kidney showed that most of the transport (>80%) in that tissue could be accounted for by function of the dicarboxylate carrier (DIC, Slc25a10) and the oxoglutarate carrier (OGC, Slc25a11), which mediate electroneutral exchange of dicarboxylates for inorganic phosphate and 2-oxoglutarate for other dicarboxylates, respectively. The identity and function of specific carrier proteins in other tissues is less certain, although the OGC is expressed in heart, liver, and brain and the DIC is expressed in liver and kidney. An additional carrier that transports 2-oxoglutarate, the oxodicarboxylate or oxoadipate carrier (ODC; Slc25a21), has been described in rat and human liver and its expression has a wide tissue distribution, although its potential function in GSH transport has not been investigated. Overexpression of the cDNA for the DIC and OGC in a renal proximal tubule-derived cell line, NRK-52E cells, showed that enhanced carrier expression and activity protects against oxidative stress and chemically induced apoptosis. This has implications for development of novel therapeutic approaches for treatment of human diseases and pathological states. Several conditions, such as alcoholic liver disease, cirrhosis or other chronic biliary obstructive diseases, and diabetic nephropathy, are associated with depletion or oxidation of the mitochondrial GSH pool in liver or kidney.
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PMID:Mitochondrial glutathione transport: physiological, pathological and toxicological implications. 1660 Jan 97

A 42-year-old woman underwent hemodialysis secondary to diabetic nephropathy. Total parathyroidectomy with forearm autograft was performed due to secondary hyperparathyroidism (HPT) complicated with calciphylaxis. Rapidly progressive enlargement of autograft with unusual "gourd-shape" developed, and then it was removed. Pathologic examination of the autograft disclosed multinodular hyperplasia. Residual parathyroid gland in the retrothyroid region was found later. Rapidly recurrent HPT originating from both the residual parathyroid tissues and the enlarged autograft within such short time after parathyroidectomy is rare in the literature. The multinodular hyperplasia pattern of the parathyroid gland may be a major factor for such rapid recurrence. In addition to good control of calcium and phosphate, regular follow-up of parathyroid hormone level and imaging studies of not only autografted gland at the forearm but also possibly residual parathyroid tissues at the neck are important for monitoring recurrence in maintenance hemodialysis patients after parathyroidectomy with forearm autograft, especially in those with pathologic type of nodular hyperplasia and calciphylaxis.
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PMID:Rapid recurrence of hyperparathyroidism from both nodularly hyperplastic autograft at forearm and residual tissues at neck after parathyroidectomy in a hemodialysis patient with calciphylaxis. 1670 1

The interaction between advanced glycation end-products (AGEs) and their receptors mediates the progressive alteration in renal architecture and loss of renal function in diabetic nephropathy. This study investigated whether nifedipine, a widely used anti-hypertensive drug, suppresses expression of monocyte chemoattractant protein-1 (MCP-1), a chemokine that mediates the recruitment of monocytes to inflammatory sites, in AGE-exposed human cultured mesangial cells. Cells were treated with 100 microg/ml AGE-bovine serum albumin (BSA) or non-glycated BSA in the presence or absence of 1 microM nifedipine or 50 nM diphenylene iodonium, an inhibitor of reduced nicotinamide-adenine dinucleotide phosphate oxidase, for 4 or 24 h. Expression of MCP-1 mRNA was measured using a semi-quantitative reverse transcription-polymerase chain reaction; MCP-1 protein production was measured using an enzyme-linked immunosorbent assay. AGEs significantly increased both MCP-1 mRNA expression and protein production in mesangial cells; this increase was blocked by both nifedipine and diphenylene iodonium. These results suggest that nifedipine could play a protective role against early diabetic nephropathy by suppressing MCP-1 overexpression via blockade of AGE signalling in mesangial cells.
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PMID:Nifedipine, a calcium-channel blocker, inhibits advanced glycation end-product-induced expression of monocyte chemoattractant protein-1 in human cultured mesangial cells. 1740 61

Diabetic nephropathy is a major cause of morbidity and mortality in diabetic patients. Two key mechanisms implicated in the development of diabetic nephropathy include advanced glycation and oxidative stress. Advanced glycation is the irreversible attachment of reducing sugars onto amino groups of proteins to form advanced glycation end products (AGEs). AGE modification of proteins may lead to alterations in normal function by inducing cross-linking of extracellular matrices. Intracellular formation of AGEs also can cause generalized cellular dysfunction. Furthermore, AGEs can mediate their effects via specific receptors, such as the receptor for AGE (RAGE), activating diverse signal transduction cascades and downstream pathways, including generation of reactive oxygen species (ROS). Oxidative stress occurs as a result of the imbalance between ROS production and antioxidant defenses. Sources of ROS include the mitochondria, auto-oxidation of glucose, and enzymatic pathways including nicotinamide adenine dinucleotide phosphate reduced (NAD[P]H) oxidase. Beyond the current treatments to treat diabetic complications such as the optimization of blood pressure and glycemic control, it is predicted that new therapies designed to target AGEs, including AGE formation inhibitors and cross-link breakers, as well as targeting ROS using novel highly specific antioxidants, will become part of the treatment regimen for diabetic renal disease.
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PMID:AGE, RAGE, and ROS in diabetic nephropathy. 1741 82

Since its experimental introduction in 1960, hemodialysis has become a widely performed and relatively safe procedure. Therapeutic strategies have been developed, and the numbers of long-term survivors of hemodialysis therapy have been increasing. Hemodialysis therapy was introduced at Sangenjaya Hospital in October 1970, and the 16 patients who have survived for more than 30 years on hemodialysis therapy since its introduction at the hospital were enrolled in this study to investigate the characteristics of long-term hemodialysis patients. For comparison, 50 patients on hemodialysis for less than 30 years were also studied (21 patients with <10 years hemodialysis, 13 with 10-20 years hemodialysis and 16 with 20-30 years hemodialysis). Background information (age, gender, and cause of renal disease), dialysis dose (single pool [sp.] Kt/V), mineral metabolism (serum phosphate), anemia management (serum hemoglobin), and nutrition (serum albumin and reduced interdialytic weight gain) were assessed. Hemodialysis was instituted at 28.7 +/- 6.4 years of age. The primary cause of end-stage renal disease was chronic glomerulonephritis in all of the patients except one, and in that patient it was polycystic kidney disease. As an index of the dialysis dose, sp. Kt/V was 1.2 +/- 0.11. As an index of mineral metabolism, serum phosphate was 5.4 +/- 0.9 mg/dL. As an index of anemia management, serum hemoglobin was 10.2 +/- 1.2 g/dL. As indexes of nutrition, serum albumin was 4.0 +/- 0.2 g/dL and interdialytic weight gain was 4.43 +/- 1.36%. The sp. Kt/V-value, serum phosphate, serum hemoglobin and interdialytic weight gain did not differ between the four different hemodialysis duration groups. Serum albumin was lower in the >30 group (4.0 +/- 0.2 g/dL) than in the <10 group (4.2 +/- 0.3 g/dL) (P = 0.046). As the duration of hemodialysis has increased, the age at hemodialysis induction has become younger. The cause of the renal failure was chronic glomerulonephritis in most of the cases. None had diabetic nephropathy. Improvement of the prognosis of patients with diabetic nephropathy is required. Most of the indexes of these patients nearly satisfied the recommended values.
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PMID:Characteristics of patients on hemodialysis therapy for more than 30 years. 1766 33

Renal nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase is an important source of oxidative stress and its expression is enhanced in the glomerulus and distal tubules of diabetic nephropathy. High glucose-induced protein kinase C signalling or renal angiotensin II signalling increases the membrane translocation of cytosolic component p47phox. NADPH oxidase-derived reactive oxygen species (ROS) in the podocytes damage the glomerular basement membrane and the slit diaphragm causing proteinuria, and mesangial and glomerular endothelial NADPH oxidase increase TGF-beta and cause collagen and fibronectin accumulation. Tubular NADPH oxidase stimulated by angiotensin II or aldosterone contributes to sodium retention and to tubulointerstitial damage. Thus, inhibition of the renal renin-angiotensin II-aldosterone system with angiotensin-converting enzyme inhibitor, angiotensin II type 1 receptor blocker or selective aldosterone inhibitor indirectly suppresses NADPH oxidase reducing renal ROS, proteinuria and glomerulosclerosis. Statins are also effective in blocking the membrane translocation of Rac, especially in diabetes with hypercholesterolemia where ROS is produced by the intrinsic NADPH oxidase and by the activated macrophages. A medical herb, picrorhiza, inhibits the membrane translocation of p47phox, is a specific inhibitor of NADPH oxidase and, more so than superoxide dismutase mimetics, may be a promising strategy for the treatment of diabetic nephropathy.
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PMID:Suppressing renal NADPH oxidase to treat diabetic nephropathy. 1766 74

Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in Japan and other Westernized countries. Over 50% of the ESRD patients die from cardiovascular events. Cardiovascular disease (CVD) in ESRD patients with diabetes mellitus (DM) are implicated in the endothelial dysfunction caused by hyperglycemia, hyperlipidemia, and hypertension, and in the vascular calcification of intimal and medial arterial blood vessels caused by hyperphosphatemia. Therefore, dietary control of hyperglycemia and hyperphosphatemia should play an important role in the management of ESRD patients with DM. Furthermore, recent findings suggest that high concentrations of serum phosphate, even if within the normal range, may be a risk factor for CVD and mortality. An in vivo study using klotho knockout mice and fibroblast growth factor 23 (FGF-23) knockout mice has revealed that correction of hyperphosphatemia and hypervitaminosis D could ameliorate the premature aging-like phenotype. A low glycemic index and low phosphate diet may provide an advantage in the prevention of aging-related diseases in healthy individuals as well as in those with chronic kidney disease.
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PMID:Advantage of a low glycemic index and low phosphate diet on diabetic nephropathy and aging-related diseases. 1787 88

The proliferation of mesangial cells (MC) in the presence of glutamine (0-20 mM) was determined in both low (5 mM) and high (25 mM) glucose-containing medium. Glutamine in a high glucose (HG) environment increased cell proliferation in a dose-dependent manner. Inhibition of glutamine:fructose 6-phosphate amidotransferase (GFAT) and of phosphodiesterase significantly reduced glutamine-induced proliferation. Supraphysiologic levels of glutamine increase MC proliferation in a HG milieu via GFAT and cAMP-dependent pathways, suggesting that glutamine could pose a risk for diabetic nephropathy.
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PMID:Glutamine enhances glucose-induced mesangial cell proliferation. 1806 May 27

The involvement of inflammatory processes has been recognized in development and/or progression of diabetic nephropathy. However, the mechanisms involved in the pathogenesis of renal inflammation have not been completely understood. In this study, we tested the hypothesis that accumulation of advanced oxidation protein products (AOPPs), which occurs in diabetes, may promote inflammatory responses in diabetic kidney. Streptozotocin-induced diabetic rats were randomized to iv injection of vehicle, native rat serum albumin (RSA), and AOPPs-modified RSA (AOPPs-RSA) in the presence or absence of oral administration of apocynin. A control group was followed concurrently. Compared with RSA- or vehicle-treated diabetic rats, AOPPs-RSA-treated animals displayed significant increase in renal macrophage infiltration and overexpression of monocyte chemoattractant protein-1 and TGF-beta1. This was associated with deteriorated structural and functional abnormalities of diabetic kidney, such as glomerular hypertrophy, fibronectin accumulation, and albuminuria. AOPP challenge significantly increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent superoxide generation in renal homogenates and up-regulated membrane expression of renal NADPH oxidase subunits p47(phox) and gp91(phox). All these AOPPs-induced perturbations in diabetic kidney could be prevented by the NADPH oxidase inhibitor apocynin. These data suggest that chronic accumulation of AOPPs may promote renal inflammation in diabetes probably through activation of renal NADPH oxidase.
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PMID:Advanced oxidation protein products promote inflammation in diabetic kidney through activation of renal nicotinamide adenine dinucleotide phosphate oxidase. 1817 76

Diabetes-induced renal complications, i.e. diabetes nephropathy, are a major cause of morbidity and mortality. The exact mechanisms mediating the negative influence of hyperglycemia on renal function are unclear, although several hypotheses have been postulated. Cellular mechanisms include glucose-induced excessive formation of reactive oxygen species, increased glucose flux through polyol pathway and pentose phosphate shunt, formation of advanced glycation end-products and activation of protein kinase C and NADPH oxidase. However, the renal effects in vivo of each and every one of these mechanisms are less clear, although recent studies have shown several major alterations predominantly in the renal medulla as a result of sustained hyperglycemia. Already during normal conditions, the renal medulla has a remarkably low oxygen tension (PO2) and a high degree of non-oxygen dependent energy metabolism. Alterations in either blood perfusion or oxygen delivery to the medullary region will have significant effects on both regional metabolism and total kidney function. Recently, sustained hyperglycemia has been shown to induce a pronounced reduction in preferentially renal medullary PO2. This review will present the current knowledge of diabetes-induced alterations in renal medullary metabolism and function, but also discuss future targets for prevention of diabetic nephropathy.
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PMID:Diabetes-induced alterations in renal medullary microcirculation and metabolism. 1822 Jun 56


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