Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathological significance of advanced glycation end product (AGE)-modified proteins deposited in several lesions is generally accounted for by their cellular interaction via the AGE receptors and subsequent acceleration of the inflammatory process. In this study, we focused on two AGE receptors-specifically, the role of SR-A in pathogenesis of diabetic nephropathy and the role of CD36 in AGE-induced downregulation of leptin by adipocytes. In terms of SR-A, diabetic wild-type mice exhibited increased urinary albumin excretion, glomerular hypertrophy, and mesangial matrix expansion, whereas SR-A-knockout mice showed reduced glomerular size and mesangial matrix area. In these diabetic SR-A-knockout mice, the number of macrophages that infiltrated into glomeruli was remarkably reduced (P < 0.05), suggesting that SR-A-dependent glomerular migration of macrophages plays an important role in the pathogenesis of diabetic nephropathy. In terms of CD36, incubation of glycolaldehyde-modified bovine serum albumin (GA-BSA) with 3T3-L1 adipocytes reduced leptin secretion by these cells. The binding of GA-BSA to these cells and subsequent endocytic degradation were effectively inhibited by a neutralizing anti-CD36 antibody. AGE-induced downregulation of leptin was protected by N-acetyl-cysteine, an antioxidant. These results indicate that the interaction of AGE ligands with 3T3-L1 adipocytes via CD36 induces oxidative stress and leads to inhibition of leptin expression by these cells, suggesting a potential link of this phenomenon to exacerbation of the insulin sensitivity in metabolic syndrome.
 ...
PMID:Pathological roles of advanced glycation end product receptors SR-A and CD36. 1603 91

Although diabetic animal models exist, no single animal model develops renal changes identical to those seen in humans. Here we show that transgenic mice that overexpress inducible cAMP early repressor (ICER Igamma) in pancreatic beta cells are a good model to study the pathogenesis of diabetic nephropathy. Although ICER Igamma transgenic mice exhibit extremely high blood glucose levels throughout their lives, they survive long enough to develop diabetic nephropathy. Using this model we followed the progress of diabetic renal changes compared to those seen in humans. By 8 weeks of age, the glomerular filtration rate (GFR) was already increased, and glomerular hypertrophy was prominent. At 20 weeks, GFR reached its peak, and urine albumin excretion rate was elevated. Finally, at 40 weeks, diffuse glomerular sclerotic lesions were prominently accompanied by increased expression of collagen type IV and laminin and reduced expression of matrix metalloproteinase-2. Nodular lesions were absent, but glomerular basement membrane thickening was prominent. At this point, GFR declined and urinary albumin excretion rate increased, causing a nephrotic state with lower serum albumin and higher serum total cholesterol. Thus, similar to human diabetic nephropathy, ICER Igamma transgenic mice exhibit a stable and progressive phenotype of diabetic kidney disease due solely to chronic hyperglycemia without other modulating factors.
 ...
PMID:Establishment of a diabetic mouse model with progressive diabetic nephropathy. 1604 20

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.
 ...
PMID:Interactions between renin angiotensin system and advanced glycation in the kidney. 1610 77

Patients receiving recombinant human erythropoietin (rHuEPO) therapy show wide variability in their responsiveness to the drug. Variables that affect rHuEPO dose requirements can be broadly divided into modificable and immutable characteristics. Most of the scientific research on rHuEPO hyporesponsiveness has focused on modificable variables (iron status, dialysis adequacy), while immutable variables such as gender, etiology of chronic renal failure (CRF) and age have been insufficiently explored. A cross sectional study was performed in order to evaluate if immutable patient characteristics determine rHuEPO dose requirements among 215 patients (52% males; mean age 66 +/- 14 years) on hemodialysis (HD) for more than twelve months. Data were collected at 10 hemodialysis units in Aragon. Patients were divided into three groups according to their gender, their cause of CRF (diabetic nephropathy, vascular nephropathy, tubulointerstitial nephropathy and primary glomerulonephritis) and their age (younger than 60 years, from 60 to 75 years, older than 75 years). Despite a similar dose of rHuEPO, women had lower mean hemoglobin (11.1 +/- 1.5 versus 11.6 +/- 1.7 g/dl; p = 0.0258) than men. The greater hemoglobin in men than women may be attributed to greater serum albumin in men (3.5 +/- 0.3 versus 3.7 +/- 0.3 mg/dl; p = 0.0001). Requirements of rHuEPO were higher in the patients with etiology of primary glomerulonephritis compared with those with the other etiologies, even those with diabetic nephropathy (p = 0.0374). The rHuE-PO doses required to obtain similar hemoglobin levels were higher in patients younger than 60 years (p = 0.0249). We conclude that women, patients with primary glomerulonephritis as cause of CRF, and patients younger than 60 years showed the highest requirements of rHuEPO doses.
 ...
PMID:[Study of immutable variables determining rHuEPO dose requirements on hemodialysis patients]. 1639 4

Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) reduces proteinuria and the rate of renal function deterioration in diabetic nephropathy and other glomerular diseases, but its role in quiescent lupus nephritis has not been established. We conducted a retrospective study to investigate the effects of ACEI/ARB on proteinuria and renal function in patients with persistent proteinuria (>1 g/day) despite resolution of acute lupus nephritis following immunosuppressive treatment. Fourteen out of 92 patients were included. The duration of treatment with ACEI/ARB was 52.1 +/- 35.7 months. The levels of proteinuria, serum albumin, serum creatinine, systolic and diastolic blood pressure were 1.10 to 6.90 g/day, 35.8 +/- 3.6 g/L, 102.54 +/- 34.48 micromol/L, 137.6 +/- 10.9 and 81.9 +/- 9.2 mmHg at baseline. Proteinuria and serum albumin showed significant sustained improvements after 6 and 24 months of treatment. Comparison of slopes for serial proteinuria, albumin and reciprocal of serum creatinine before and after treatment showed significant improvements in six (43%), eight (57%) and two patients, respectively. At last follow-up proteinuria remained significantly lower (0.36 g/day, P = 0.043) and albumin higher (41.3 +/- 2.2 g/L, P = 0.023). Eleven (78.6%) patients had proteinuria improved by >50%, and five had insignificant proteinuria at last follow-up. Systolic blood pressure was significantly reduced from 6 months onwards, but this did not correlate with proteinuria reduction. Diastolic blood pressure, serum creatinine, creatinine clearance, anti-dsDNA, C3 and haemoglobin were not altered. We conclude that ACEI/ARB effectively reduces proteinuria and improves serum albumin in patients with persistent proteinuria despite quiescent lupus nephritis.
 ...
PMID:Angiotensin inhibition or blockade for the treatment of patients with quiescent lupus nephritis and persistent proteinuria. 1642 74

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.
 ...
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

Cognitive impairment in elderly diabetic patients has generated considerable interest recently; however, the mechanism of the impairment remains to be elucidated. In the current study, factors associated with cognitive dysfunction in old diabetic patients were explored. A Mini Mental State Examination (MMSE) was performed on 907 of 1173 registered elderly Japanese diabetic subjects. To characterize the clinical features of diabetes, we examined indices of glycemic control, lipid metabolism, blood pressure and complications. Single regression analysis adjusted for age showed that shorter height, higher GDS 15 scores, lower serum albumin, history of cerebrovascular disease, the existence of diabetic nephropathy, no smoking habit, no drinking habit, and no occupation were associated with lower MMSE scores. Multiple regression analysis demonstrated that age (odds ratio (OR)=1.079; 95% confidence interval (CI)=1.011-1.150), GDS 15 scores (OR=1.139; 95% CI=1.045-1.243), serum albumin (OR=0.336; 95% CI=0.174-0.745), and history of cerebrovascular disease (OR=3.011; 95% CI=1.578-5.748) were the variables significantly associated with having lower MMSE scores.
 ...
PMID:Factors associated with lower Mini Mental State Examination scores in elderly Japanese diabetes mellitus patients. 1743 48

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.
 ...
PMID:Characteristics of patients on hemodialysis therapy for more than 30 years. 1766 33

Advanced glycation endproducts (AGEs) and a receptor for AGEs (RAGE) have been linked in the pathogenesis of diabetic nephropathy. RAGE is usually localized to podocytes and is increased in diabetes. RAGE activation increases reactive oxygen species production, which mediates hyperglycemia-induced podocyte apoptosis in early diabetic nephropathy. Here, we examined the interaction of AGE and RAGE on podocyte apoptosis. When we exposed murine cultured podocytes to bovine serum albumin (BSA) that was modified by AGEs or to carboxymethyl-lysine BSA, more apoptosis was found when compared with unmodified BSA. Similarly, more podocytes underwent detachment and apoptosis when cultured on AGE-modified collagen IV than on native collagen IV. AGEs isolated from sera of patients with chronic kidney disease also caused apoptosis of podocytes. Apoptosis was diminished by small interference RNA (siRNA) for RAGE in podocytes exposed to AGE-BSA, but not to AGE-modified collagen IV. Both AGE- and carboxymethyl-lysine modified-BSA activated p38MAP kinase and inhibition of this kinase reduced the apoptotic effect of AGE-BSA. Exposure to AGE-BSA was associated with Akt dephosphorylation and FOXO4 transcriptional activation leading to an increase in the expression of an effector protein of apoptosis, Bim. siRNA for FOXO4 abolished AGE-BSA-induced apoptosis of podocytes. Our study suggests that an AGE-RAGE interaction contributes to podocyte apoptosis by activation of the FOXO4 transcription factor.
 ...
PMID:Advanced glycation endproducts induce podocyte apoptosis by activation of the FOXO4 transcription factor. 1766 83

Diabetic nephropathy is the most important cause of ESRD. The aim of this study was to develop a risk score from risk predictors for ESRD, with and without death, in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study and to compare ability of the ESRD risk score and its components to predict ESRD. The risk score was developed from coefficients of independent risk factors from multivariate analysis of baseline variables and equals (1.96 x log [urinary albumin:creatinine ratio]) - (0.78 serum albumin [g/dl]) + (1.28 x serum creatinine [mg/dl]) - (0.11 x hemoglobin [g/dl]). It was robust with respect to severity of nephropathy, gender, race, and treatment group. The risk score for ESRD or death was comparable. The four risk predictors for progression of kidney disease were independent of therapy. For combined treatment groups, the hazard ratio between the fourth and first quartiles of the ESRD risk score was 49.0, as compared with the corresponding hazard ratios for each component: 14.7 for urinary albumin:creatinine ratio, 9.2 for serum creatinine, 5.5 for hemoglobin, and 10.2 for serum albumin. The RENAAL risk scores for ESRD with or without death emphasize the importance of identification of level of albuminuria, serum albumin, serum creatinine, and hemoglobin to predict development of ESRD in patients with type 2 diabetes and nephropathy. Although albuminuria is a strong risk factor for ESRD, the contribution of serum albumin, serum creatinine, and hemoglobin level further enhances prediction of ESRD. Future trials with a similar patient population and outcomes measures should consider adjusting analyses for baseline risk factors.
 ...
PMID:Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy: the RENAAL study. 1769 65


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>