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George Jerums

Publications and source records attributed to George Jerums.

46 records · Page 3Linked to original sources
PubMed2002

Expression of the slit-diaphragm protein, nephrin, in experimental diabetic nephropathy: differing effects of anti-proteinuric therapies.

BACKGROUND: Mutations in the gene coding for the podocyte slit-pore membrane protein, nephrin, are responsible for the Finnish-type congenital nephrotic syndrome. The present study sought to examine whether nephrin expression may also be altered in experimental diabetes, and how such changes related to the development of proteinuria. In addition, the study also sought to examine nephrin expression in animals treated with different anti-proteinuric therapies. METHODS: Nephrin gene expression and localization were examined in rats with streptozotocin-induced diabetes at 6 months duration (proteinuric phase) and at 7 days (pre-proteinuric phase). In addition, the effects of anti-proteinuric drug therapies were also assessed in long-term diabetic rats, treated with either the angiotensin-converting enzyme inhibitor perindopril, or the blocker of advanced glycation end-product formation, aminoguanidine. Nephrin expression was determined using quantitative real-time PCR and in situ hybridization. RESULTS: When compared with control animals, nephrin expression was reduced in the late proteinuric phase (45% reduction vs controls, P<0.01) but not in the early, pre-proteinuric phase of experimental diabetic nephropathy. While ACE inhibition and aminoguanidine both reduced proteinuria, only the former attenuated the diabetes-associated reduction in nephrin expression. CONCLUSIONS: These findings suggests that reduction in nephrin may be a determinant of glomerular hyperpermeability in diabetic nephropathy. Attenuation of these changes with ACE inhibition suggest that this mechanism may contribute to the anti-proteinuric effects of this, but not all classes of drug which reduce urinary protein in diabetic nephropathy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Modulation of nephrin in the diabetic kidney: association with systemic hypertension and increasing albuminuria.

OBJECTIVE: Nephrin, a cytoskeletal protein which localizes to the slit pore of podocytes, may play a role in proteinuria. This study examines the possible relationship between nephrin expression and albuminuria in normotensive and hypertensive diabetic rats. METHODS: Streptozotocin diabetes was induced in both Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Diabetic and control animals were sacrificed and the kidneys obtained after 8, 16 and 24 weeks. The glomerular filtration rate (GFR) and albuminuria were also measured. Glycaemic control was assessed by measurement of plasma glucose and glycated haemoglobin (HbA1c). Nephrin gene expression was quantitated by real-time polymerase chain reaction (PCR) and localized by in situ hybridization. Nephrin protein expression was localized by immunohistochemistry and quantitated. RESULTS: Following a transient rise at 8 weeks in the diabetic SHR (P < 0.05 versus control SHRs), nephrin gene expression, as determined by real-time PCR, was significantly decreased at 16 and 24 weeks (P < 0.05 versus control SHRs). In situ hybridization confirmed similar changes in nephrin gene expression, which were confined to the glomeruli. This reduction in glomerular nephrin gene expression was associated with increasing albuminuria at 16 and 24 weeks in diabetic SHRs. There were no significant changes in nephrin gene expression, either by real-time reverse transcription polymerase chain reaction or in situ hybridization, observed in normotensive diabetic WKY rats, in the context of much less albuminuria in this group. Immunohistochemistry for nephrin protein revealed a greater depletion in renal nephrin content in SHR than in WKY rats after 24 weeks of diabetes. CONCLUSION: Reduction in renal nephrin gene and protein expression is closely associated with the development of albuminuria, as observed in an experimental model of diabetes and hypertension.

Albuminuria↗
PubMed2002

Albuminuria in hypertension is linked to altered lysosomal activity and TGF-beta1 expression.

Increased intraglomerular pressure is considered a major factor for increased albumin excretion in hypertension. However, other factors should also be considered because recent studies in both humans and rats have demonstrated that proteins undergoing filtration and renal passage are extensively modified by renal cell lysosomal processing; >95% of albumin is degraded to peptides that are not detected by routine immunochemical assays. Changes in postglomerular lysosomal processing may therefore be responsible for the increased intact albumin excreted in hypertension-related kidney disease. We hypothesize that transforming growth factor-beta, which is known to decrease lysosomal activity, may be upregulated in hypertension and may play a role in increased intact albumin excretion. The aims of this study were to determine the effect that hypertension has on (1) renal cell lysosomal processing of albumin and dextran sulfate, (2) glomerular permeability, and (3) renal transforming growth factor-beta(1) expression. Spontaneously hypertensive rats and Wistar-Kyoto rats were used at 8, 16, and 24 weeks. We demonstrate that albuminuria in hypertension is linked to an inhibition of lysosomal processing as determined by (1) size exclusion chromatography analysis of urinary [(14)C]albumin structural integrity and (2) ion exchange analysis of urinary [(3)H]dextran sulfate. This inhibition gives rise to an increased proportion of radioimmunoassay detectable (intact) albumin and intact dextran sulfate independent of changes in glomerular capillary wall permeability as determined by the fractional clearance of [(3)H]Ficolls of various radii. These changes may be correlated with increased renal transforming growth factor-beta(1) expression.

Albuminuria↗
PubMed2002

Treatment of microalbuminuria in patients with type 2 diabetes mellitus.

The incidence of type 2 diabetes mellitus is increasing world-wide, and is now one of the leading causes of end-stage renal disease in Western countries. Type 2 diabetes mellitus is also a major risk factor for cardiovascular events. Therefore, the early identification of patients at greatest risk, and the subsequent initiation of renal and cardiovascular protective treatments, are of the utmost importance. Microalbuminuria refers to a subclinical increase in urinary albumin excretion. By definition it corresponds to an albumin excretion rate of 20 to 200 microg/min (30 to 300 mg/day) or an albumin to creatinine ratio (mg/mmol) of 2.5 to 25 in males and 3.5 to 35 in females. Microalbuminuria is an important clinical finding because it is not only associated with an increased risk of progression to overt proteinuria (macroalbuminuria) and renal failure, but also cardiovascular events. In patients who progress to overt nephropathy, microalbuminuria usually precedes macroalbuminuria by an interval of 5 to 10 years. In patients with type 1 diabetes mellitus, blood pressure increases and renal function declines after the onset of macroalbuminuria. However, in patients with type 2 diabetes mellitus, hypertension and a decline in renal function may occur when albumin excretion is still in the microalbuminuric range. Large clinical trials have demonstrated that achieving tight glycemic (i.e. glycosylated hemoglobin < 7.0%) and blood pressure (i.e. < 130/85mm Hg) control retards the progression of renal disease. There is accumulating evidence to suggest that the use of antihypertensive agents which target the renin-angiotensin system (RAS) can slow the progression of renal disease and provide cardioprotection in patients with type 2 diabetes mellitus and microalbuminuria. Antihypertensive agents which target the RAS also appear to have advantages over and above reductions in systemic blood pressure. In summary, the annual screening of patients with type 2 diabetes mellitus for microalbuminuria, and the initiation of measures to retard the progression of renal and cardiovascular disease, are now considered part of routine clinical practice. In particular, the finding of microalbuminuria should provoke an intensified modification of the common risk factors for renal and cardiovascular disease, that is hyperglycemia, hypertension, dyslipidemia and smoking. Antihypertensive therapy in patients with microalbuminuria and type 2 diabetes mellitus should be initiated with angiotensin converting enzyme (ACE) inhibitors or angiotensin-II type 1 receptor antagonists.

Albuminuria↗
PubMed2002

Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy.

The effect of ACE inhibition on the formation of advanced glycation end products (AGEs) and oxidative stress was explored. Streptozocin-induced diabetic animals were randomized to no treatment, the ACE inhibitor ramipril (3 mg/l), or the AGE formation inhibitor aminoguanidine (1 g/l) and followed for 12 weeks. Control groups were followed concurrently. Renal AGE accumulation, as determined by immunohistochemistry and both serum and renal fluorescence, were increased in diabetic animals. This was attenuated by both ramipril and aminoguanidine to a similar degree. Nitrotyrosine, a marker of protein oxidation, also followed a similar pattern. The receptor for AGEs, gene expression of the membrane-bound NADPH oxidase subunit gp91phox, and nuclear transcription factor-kappaB were all increased by diabetes but remained unaffected by either treatment regimen. Two other AGE receptors, AGE R2 and AGE R3, remained unchanged for the duration of the study. The present study has identified a relationship between the renin-angiotensin system and the accumulation of AGEs in experimental diabetic nephropathy that may be linked through oxidative stress

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

A low-sodium diet potentiates the effects of losartan in type 2 diabetes.

OBJECTIVE: Diabetic subjects have a high prevalence of hypertension, increased total body exchangeable sodium levels, and an impaired ability to excrete a sodium load. This study assessed the effect of dietary sodium restriction on the efficacy of losartan in hypertensive subjects with type 2 diabetes and albumin excretion rates of 10-200 microg/min. RESEARCH DESIGN AND METHODS: In this study, 20 subjects were randomized to losartan 50 mg/day (n = 10) or placebo (n = 10). Drug therapy was given in two 4-week phases separated by a washout period. In the last 2 weeks of each phase, patients were assigned to low- or regular-sodium diets, in random order. In each phase, 24-h ambulatory blood pressure, urinary albumin-to-creatinine ratio (ACR), and renal hemodynamics were measured. RESULTS: Achieved urinary sodium on a low-sodium diet was 85 +/- 14 and 80 +/- 22 mmol/day in the losartan and placebo groups, respectively. In the losartan group, the additional blood pressure-lowering effects of a low-sodium diet compared with a regular-sodium diet for 24-h systolic, diastolic, and mean arterial blood pressures were 9.7 mmHg (95% confidence interval [CI], 2.2-17.2; P = 0.002), 5.5 mmHg (2.6-8.4; P = 0.002), and 7.3 mmHg (3.3- 11.3; P = 0.003), respectively. In the losartan group, the ACR decreased significantly on a low-sodium diet versus on a regular-sodium diet (-29% [CI -50.0 to -8.5%] vs. + 14% [-19.4 to 47.9%], respectively; P = 0.02). There was a strong correlation between fall in blood pressure and percent reduction in the ACR (r = 0.7, P = 0.02). In the placebo group, there were no significant changes in blood pressure or ACR between regular- and low-sodium diets. There were no significant changes in renal hemodynamics in either group. CONCLUSIONS: These data demonstrated that a low-sodium diet potentiates the antihypertensive and antiproteinuric effects of losartan in type 2 diabetes. The blood pressure reduction resulting from the addition of a low-sodium diet to losartan was of similar magnitude to that predicted from the addition of a second antihypertensive agent.

Albuminuria↗
PubMed2002

Urinary transforming growth factor-beta excretion in patients with hypertension, type 2 diabetes, and elevated albumin excretion rate: effects of angiotensin receptor blockade and sodium restriction.

OBJECTIVE: Transforming growth factor-beta (TGF-beta) is a prosclerotic growth factor implicated in the pathogenesis of diabetic nephropathy. In addition to high glucose, other factors implicated in renal fibrosis and increased TGF-beta synthesis include angiotensin II and high dietary sodium intake. The aim of this study was to examine the effect of angiotensin receptor blockade (ARB) and dietary sodium restriction on the plasma concentration and urinary excretion of TGF-beta in hypertensive patients with type 2 diabetes and elevated albumin excretion rate (AER). RESEARCH DESIGN AND METHODS: Twenty-one subjects with hypertension and AER between 10 and 200 microg/min were randomized to receive either 50 mg losartan daily (n = 11) or placebo (n = 10). Drug therapy was given in two 4-week phases, separated by a 4-week washout period. In the last 2 weeks of each phase, patients were assigned to regular- or low-sodium diets in random order. Parameters measured at week 0 and 4 of each phase included plasma TGF-beta concentration, TGF-beta urinary excretion, AER, clinic mean arterial blood pressure, and urinary sodium excretion. RESULTS: Plasma TGF-beta was unaffected by losartan treatment or sodium intake. In the losartan group, urinary TGF-beta excretion decreased by 23.2% (-39.2 and 13.6) [median (interquartile range)] and 38.5% (-46.8 and -6.1) in the regular- and low-sodium phases, respectively (P < 0.05 for drug effect). In the placebo group, median changes of 0.0% (-12.1 and 44.4) and 0.0% (-29.2 and 110.7) occurred in the regular- and low-sodium phases, respectively. Sodium restriction did not affect urinary TGF-beta excretion in either losartan- or placebo-treated patients (P = 0.54 for overall dietary effect), and there was no evidence of interaction between drug and diet (P = 0.29). CONCLUSIONS: In hypertensive type 2 diabetic patients with elevated AER, the ARB losartan, but not sodium restriction, reduced urinary TGF-beta excretion. These data suggest that the renoprotective effects of losartan in patients with type 2 diabetes and nephropathy may include a reduction in renal TGF-beta production.

Albuminuria↗
PubMed2001

Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy.

Profibrotic cytokines and the formation of advanced-glycation end products (AGE) have both been implicated in the pathogenesis of glomerulosclerosis in diabetic kidney disease. However, tubulointerstitial pathology is also an important determinant of progressive renal dysfunction in diabetic nephropathy. This study sought to investigate the expression of profibrotic growth factors and matrix deposition in the glomerulus and the tubulointerstitium and to examine the effect of blocking AGE formation in experimental diabetic nephropathy. Thirty-six male Sprague-Dawley rats were randomized into control and diabetic groups. Diabetes was induced in 24 rats by streptozotocin. Twelve diabetic rats were further randomized to receive the inhibitor of AGE formation, aminoguanidine (1 g/l drinking water). At 6 mo, experimental diabetes was associated with a three-fold increase in expression of transforming growth factor (TGF)-beta1 (P < 0.01 versus control) and five-fold increase in platelet-derived growth factor (PDGF)-B gene expression (P < 0.01 versus control) in the tubulointerstitium. In situ hybridization demonstrated a diffuse increase in both TGF-beta1 and PDGF-B mRNA in renal tubules. Aminoguanidine attenuated not only the overexpression of TGF-beta1 and PDGF-B but also reduced type IV collagen deposition in diabetic rats (P < 0.05). TGF-beta1 and PDGF mRNA within glomeruli were also similarly increased with diabetes and attenuated with aminoguanidine. The observed beneficial effects of aminoguanidine on the tubulointerstitium in experimental diabetes suggest that AGE-mediated expression of profibrotic cytokines may contribute to tubulointerstitial injury and the pathogenesis of diabetic nephropathy.

Animals↗
PubMedDate not supplied

Renal processing of albumin in diabetes and hypertension in rats: possible role of TGF-beta1.

BACKGROUND/AIMS: Recent studies show that albuminuria may be the result of changes in post-glomerular cellular uptake and processing of albumin. This study aims to determine whether this processing is disrupted in diabetes and/or hypertension. METHODS: Diabetes (d) was induced using streptozotocin in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) and studied after 8, 16 and 24 weeks of disease. Intact albumin excretion was determined by radioimmunoassay. Total albumin was determined by [(14)C]albumin. Lysosomal activity was determined by dextran sulfate desulfation. Renal TGF-beta1 and transforming growth factor-beta1 inducible gene-h3 mRNA (betaig-h3) expression was determined by real time RT-PCR. RESULTS: SHR-c rats exhibited an increase in intact albuminuria without significant change in total albumin excretion (intact plus albumin-derived peptides). For WKY-d rats, intact albuminuria developed initially, followed by an increase in total albumin excretion primarily in the form of albumin peptides (peptiduria). SHR-d rats exhibited both increases in peptiduria and intact albuminuria. There was no increase in glomerular permeability at 24 weeks for polydisperse [(3)H]Ficoll in all groups. Increased renal TGF-beta1 and betaig-h3 expression was correlated with a decrease in dextran sulfate desulfation and increased intact albuminuria independent of peptiduria. CONCLUSION: Increased albumin excretion in hypertension and/or diabetes is manifested in different forms independent of glomerular permeability.

Albumins↗