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Biomedical subjects

Mark E Cooper

Publications and source records attributed to Mark E Cooper.

At least 109 records · Page 6Linked to original sources
PubMed2002

Attenuation of tubular apoptosis by blockade of the renin-angiotensin system in diabetic Ren-2 rats.

BACKGROUND: Tubular atrophy is a major feature of most renal diseases and is closely associated with loss of renal function. The present study sought to investigate tubular epithelial cell apoptosis in experimental diabetic nephropathy and to explore the role of pro-apoptotic [transforming growth factor-beta (TGF-beta) and anti-apoptotic growth factors [epidermal growth factor (EGF)]. The effects of renoprotective therapy with blockade of the renin-angiotensin system (RAS) also were examined. METHODS: Six-week-old female Ren-2 rats were injected with streptozotocin (STZ) and maintained diabetic for 12 weeks. Further groups of diabetic rats were treated with the angiotensin-converting enzyme (ACE) inhibitor, perindopril, or the angiotensin II type 1 (AT1) receptor antagonist, valsartan, for 12 weeks. RESULTS: Widespread apoptosis, identified immunohistochemically by single stranded DNA and TUNEL, was noted in the tubules of diabetic Ren-2 rats. These changes were associated with a 50% decrease in EGF expression and a twofold increase in TGF-beta1 mRNA. Treatment of diabetic Ren-2 rats with either valsartan (20 mg/kg/day) or perindopril (6 mg/kg/day) reduced apoptosis to control levels in association with supranormal levels of EGF mRNA (P < 0.01) and a reduction in TGF-beta1 gene expression (P < 0.05) to that of control rats. CONCLUSIONS: Tubular apoptosis is a prominent feature of diabetic Ren-2 rats that is attenuated by blockade of the RAS in association with modulation of pro- and anti-apoptotic growth factor expression.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Renal ischemia-reperfusion increases endothelial VEGFR-2 without increasing VEGF or VEGFR-1 expression.

BACKGROUND: Hypoxia is a potent stimulus to angiogenesis. Expression of the angiogenic growth factor vascular endothelial growth factor (VEGF) and its receptors (VEGFR-1 and VEGFR-2) is up-regulated by hypoxia in a variety of organs and cell lines. We have previously reported that VEGF expression is not increased in renal ischemia-reperfusion injury, although tubular cells concentrate VEGF at their basolateral surface. In this study we assess whether altered VEGF receptor expression compensates for the lack of VEGF regulation during renal ischemia-reperfusion injury. METHODS: VEGFR-1 mRNA expression was assessed by Northern blotting and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). VEGFR-2 mRNA expression was analyzed by Northern blotting and in situ hybridization (ISH), while VEGFR-2 protein expression was studied using immunohistochemistry. VEGF mRNA expression was assessed by ISH. RESULTS: VEGFR-2 mRNA and protein expression were up-regulated without an increase in VEGF or VEGFR-1 expression. Normal kidneys showed low-level VEGFR-2 mRNA and protein expression in glomerular and peritubular endothelium. Following ischemia and ischemia-reperfusion, a marked increase in VEGFR-2 mRNA and protein expression was seen (2- to 4-fold). Most prominent was VEGFR-2 mRNA up-regulation in the glomerulus although, surprisingly, increased protein was not demonstrated here. ISH showed that VEGF mRNA was not up-regulated in this model, confirming our previous findings for VEGF. CONCLUSION: VEGF and VEGFR-1 expression are not increased by renal ischemia and ischemia-reperfusion injury. Instead, endothelial expression of VEGFR-2 is increased. VEGFR-2 up-regulation in renal ischemia-reperfusion may be important in mediating the mitogenic and anti-apoptotic actions of VEGF on endothelial cells, thereby preserving the integrity of the endothelium and the potential for blood supply to ischemic tissues.

Animals↗
PubMed2002

Up-regulation of components of the renin-angiotensin system in the bile duct-ligated rat liver.

BACKGROUND & AIMS: Angiotensin II (ANG II) has profibrotic actions in the heart and kidney, whereas blockade of the renin angiotensin system (RAS) attenuates injury. This study examines whether the RAS is present in the liver and examines its regulation in the bile duct-ligation model of hepatic fibrogenesis. METHODS: Sham-operated and bile duct-ligated (BDL) Sprague-Dawley rats were studied. Gene and protein expression of hepatic renin, angiotensinogen, angiotensin-converting enzyme (ACE), and the angiotensin receptors AT1 and AT2 were assessed using real-time reverse-transcription polymerase chain reaction, in vitro autoradiography, and immunohistochemistry. RESULTS: Angiotensinogen and renin messenger RNA were detected in sham liver but were not increased following BDL. Angiotensinogen protein was widely distributed in hepatocytes in both normal and injured livers, but in BDL livers, it was also expressed within areas of active fibrogenesis. Both ACE and AT1 receptor genes were up-regulated following BDL. The low level of ACE activity in sham animals was significantly increased in areas of active fibrogenesis in BDL livers. The AT1 receptor was present in both normal and diseased liver parenchyma, with increased AT1 receptor binding seen in fibrotic areas in the diseased liver. The AT2 receptor gene was not detected in normal or diseased liver. CONCLUSIONS: Key elements of the RAS are present in normal liver tissue, and there is major up-regulation of the system in the bile duct-ligated liver. These findings are in keeping with recent experimental studies that have demonstrated antifibrotic effects of RAS blockade in the bile duct-ligated liver.

Animals↗
PubMed2002

Role of nephrin in renal disease including diabetic nephropathy.

Nephrin, a newly described protein, has been localized to the slit membrane between adjacent podocytes of the glomerulus. Its discovery followed the demonstration of the gene NPHS1 and its mutation, resulting in the absence of the protein product, nephrin, in the congenital nephrotic syndrome of the Finnish type. The link between permutations in nephrin expression and proteinuria has been shown in animal models by using neutralizing antibodies or studying mice with inactivation of the nephrin gene. Moreover, the expression of nephrin has been shown to be reduced in various animal models of proteinuric renal disease. The relationship between changes in nephrin expression and proteinuric renal disease in humans is not fully elucidated, with a reduction in expression of this protein reported in a range of renal diseases. Diabetic nephropathy, one of the major causes of end-stage renal disease, is associated with substantial proteinuria and in experimental models with a reduction in slit pore density. In experimental models of diabetes, nephrin expression has been described as being transiently increased in the first 8 weeks of diabetes, followed in longer-term studies with reduced nephrin expression in association with increasing proteinuria. An angiotensin II-receptor blocker has been shown to prevent depletion in glomerular nephrin expression in the diabetic kidney. Human studies in both type 1 and type 2 diabetes suggest down-regulation of nephrin expression in the diabetic kidney and it has been postulated that these changes may play a role in the pathogenesis of diabetic nephropathy, specifically the development of proteinuria in this condition. Although there are other proteins involved in the structure of the epithelial podocyte and specifically the slit pore, nephrin seems to play a pivotal role in preventing passage of protein through the glomerular barrier. Furthermore, it is suggested that the antiproteinuric effects of inhibition of the renin-angiotensin system may partly relate to the effects of these agents on nephrin expression.

Animals↗
PubMed2002

Nephrin expression in the post-natal developing kidney in normotensive and hypertensive rats.

Nephrin is a slit diaphragm protein and its expression in the developing kidney is largely unknown. In this study, we explored the expression of nephrin in the developmental kidney in spontaneously hypertensive (SHR) and in Wistar-Kyoto (WKY) rats at different time points, from day 5 after birth to adulthood. Real time RT-PCR, in situ hybridization and immunohistochemistry were used to assess and quantify gene and protein expression of nephrin in the kidney. SHR had hypertension at week 10 and albuminuria at week 20. Nephrin expression in both SHR and WKY increased from day 5 to adulthood. Furthermore, both gene and protein expression of nephrin were significantly lower in SHR after birth when compared to WKY at the same age. These findings suggest that both in normotensive and hypertensive rats, nephrin expression increased from birth to the adult age and that down-regulation of nephrin in SHR evident from the early developmental kidney to adulthood may contribute to the development of albuminuria in adult SHR.

Albuminuria↗
PubMed2002

Combination antihypertensive therapy in the treatment of diabetic nephropathy.

Diabetic nephropathy is one of the major causes of end-stage renal disease and is often associated with other macrovascular complications such as ischemic heart disease and peripheral vascular disease. Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (AIIR) have both been shown to have a protective effect on the progression of diabetic nephropathy and have thus become the first choice for treatment of hypertension and/or renal involvement in patients with diabetes. However, most of these patients, especially those with type 2 diabetes, require two of more medications in order to reduce their blood pressure to the levels, which have been proposed in recently published consensus papers. These target blood pressure levels are 130/80 mm Hg in diabetic subjects with proteinuria of up to 1 g/day and 125/75 mm Hg in those with proteinuria in excess of 1 g/day. Combinations of different medications may have a synergistic effect. Some of the early studies using a combination of either a nondihydropyridine or a dihydropyridine calcium channel blocker with ACE-I demonstrated a synergistic effect on proteinuria in patients with diabetic nephropathy. However, these studies have not been substantiated, but calcium channel blockers, with their proven ability to reduce blood pressure, play an important role in the treatment of patients with diabetic nephropathy and hypertension. The combination of ACE-I with AIIR may have several theoretical advantages. Many studies using this combination have been performed in animal models of diabetes and in patients with diabetic and nondiabetic renal disease. Some of these studies have demonstrated a synergistic effect of the combination on proteinuria or hypertension, but the results have not been consistent in all studies. It may be concluded that, until additional studies provide more convincing evidence, this combination could be used in patients whose proteinuria or hypertension has not responded to either one of the agents as monotherapy or to a combination of other medications.

Angiotensin Receptor Antagonists↗
PubMed2002

Combined inhibition of neutral endopeptidase with angiotensin converting enzyme or endothelin converting enzyme in experimental diabetes.

OBJECTIVE: The effects of combined inhibition of neutral endopeptidase (NEP) with either angiotensin-converting enzyme (ACE), or endothelin-converting enzyme (ECE) on blood pressure, urinary albumin excretion and heart weight were explored in experimental diabetes. DESIGN: Streptozotocin-induced diabetic Sprague-Dawley rats were treated with vehicle, the NEP/ACE inhibitor S 21402, the NEP/ECE inhibitor CGS 26303, the NEP inhibitor SCH 42495, the ACE inhibitor captopril or the endothelin receptor antagonist bosentan for 4 weeks. METHODS: Blood pressure was measured by tail-cuff method and radiotelemetry. Albuminuria, plasma renin activity and plasma atrial natriuretic peptide (ANP) were determined by radioimmunoassay. NEP binding was assessed by in vitro quantitative autoradiography. Metabolic and biochemistry parameters including food intake, 24-h urine volume, plasma glucose, glycated hemoglobin, glomerular filtration rate (GFR) and urinary sodium excretion were also determined. RESULTS: Mean blood pressure over the 4-week study period after commencement of treatment was reduced to a similar extent by a range of treatments including the ACE inhibitor, NEP/ACE inhibitor, endothelin receptor antagonist, NEP/ECE inhibitor, but not the NEP inhibitor, compared with vehicle-treated diabetic rats. Heart to body weight ratio in diabetic rats was only reduced by the NEP/ACE and the NEP/ECE inhibitor. Increased albuminuria in diabetic rats (1.1 times/divided by 1.2 mg/day) was reduced by the NEP/ACE (0.6 times/divided by 1.2 mg/day) and the NEP/ECE inhibitors (0.4 times/divided by 1.2 mg/day). Renal NEP was reduced by the NEP/ACE inhibitor (35 +/- 4%) or NEP/ECE inhibitor (38 +/- 4%) as well as by the pure NEP inhibitor (27 +/- 4%) compared with the untreated diabetic group. Other abnormal metabolic and biochemical parameters in diabetic rats were not influenced by any drug treatment. CONCLUSIONS: Combined inhibition of NEP/ACE or NEP/ECE confers beneficial effects on blood pressure, albuminuria and heart to body weight ratio in experimental diabetes.

Albuminuria↗
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

Renal expression of angiotensin receptors in long-term diabetes and the effects of angiotensin type 1 receptor blockade.

OBJECTIVE: The aims of this study were to assess the renal expression of angiotensin type 1 (AT1) and type 2 (AT2) receptors in diabetic spontaneously hypertensive rats (SHR) and the effect of AT1 receptor blockade on the expression of these receptors. DESIGN: Diabetes was induced by injection of streptozotocin in SHRs. Irbesartan, an AT1 receptor antagonist, was given to diabetic SHRs for 32 weeks (15 mg/kg per day, n = 10). Diabetic (n = 10) and non-diabetic SHRs (n = 10) were studied concurrently. A separate group of control and diabetic Wistar-Kyoto (WKY) rats were also evaluated. METHODS: Gene and protein expressions of the AT1 and AT2 receptor were assessed by reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry with specific antibodies andin vitro autoradiography with [125I]Sar(1), Ile(8) angiotensin II or [125I]CGP42112B. RESULTS: Both AT1 and AT2 receptor mRNA levels in the kidney were reduced in diabetic SHRs compared to non-diabetic SHRs. Immunohistochemistry staining with specific antibodies showed a similar reduction in glomerular and tubulo-interstitial staining for both AT1 and AT2 receptors. Reduced binding for the AT1 and AT2 receptor was found in the kidney of diabetic SHRs. Diabetic SHRs developed albuminuria and had glomerular and tubulo-interstitial injury, which were prevented by treatment with irbesartan. Reduced expression of the AT1 receptor, but not the AT2 receptor, in diabetic SHRs was prevented by treatment with irbesartan. In diabetic WKY rats no such reduction in AT1 expression was observed, although there was a trend for reduced AT2 receptor expression. CONCLUSIONS: These findings demonstrated that renal expression of both AT1 and AT2 receptor was reduced in long-term diabetic SHRs and that blockade of the AT1 receptor had disparate effects on expression of angiotensin II receptor subtypes.

Angiotensin Receptor Antagonists↗
PubMed2002

Hypertension and diabetes.

Hypertension is often associated clinically with diabetes either as part of the insulin resistance syndrome or as a manifestation of renal disease. Elevated systemic blood pressure accelerates the progression of both microvascular and macrovascular complications in diabetes. Agents that interrupt the renin-angiotensin system confer renoprotection via a range of hemodynamic and nonhemodynamic mechanisms. Recent clinical trials confirm that these agents confer renoprotection in type 1 and type 2 diabetic patients with early or advanced renal disease. Hypertension also appears to accelerate vascular and cardiac abnormalities in diabetes, including increased atherosclerosis, arterial stiffness, left ventricular hypertrophy and diastolic dysfunction. A number of recently published and ongoing trials are exploring the role of aggressive antihypertensive treatment with a range of antihypertensive drugs in diabetic subjects at risk of or with macrovascular disease.

Cardiovascular Diseases↗
PubMed2002

Angiotensin type 2 receptor antagonism confers renal protection in a rat model of progressive renal injury.

The role of the angiotensin type 2 (AT(2)) receptor in the pathogenesis of progressive renal injury has not been previously elucidated. The renal expression of the AT(1) and AT(2) receptors in subtotally nephrectomized rats (STNx) and the effects of AT(2) receptor blockade on renal injury were explored. Reduced renal expression of the AT(1) but not the AT(2) receptor was observed in STNx by reverse transcription-PCR, by in vitro autoradiography, and by immunohistochemical staining. The STNx rats were randomly assigned to AT(1) receptor antagonist valsartan, AT(2) receptor antagonist PD123319, or the combination of both for 4 wk. Increased proteinuria in STNx rats was reduced by PD123319 but to a lesser degree when compared with valsartan. Reduced gene and protein expression of the slit diaphragm protein nephrin was prevented by either valsartan or PD123319. Expression of osteopontin, proliferating cell nuclear antigen, and monocyte/macrophage infiltration was increased in STNx rats and was reduced by both AT(1) and AT(2) receptor antagonists. These effects of AT(2) receptor antagonism were observed in the presence of increased BP in STNx rats. These findings suggest that blockade of the AT(2) receptor alone confers a degree of renal protection; in particular, it seems that the combination of the AT(1) and AT(2) receptor antagonists may confer additive renal effects than either receptor antagonist as monotherapy.

Angiotensin Receptor Antagonists↗
PubMed2002

Renal connective tissue growth factor induction in experimental diabetes is prevented by aminoguanidine.

The aim of this study was to determine whether aminoguanidine (AG), an inhibitor of advanced glycation, prevents expression of the profibrotic cytokine, connective tissue growth factor (CTGF), as well as accumulation of the previously reported CTGF-dependent matrix protein, fibronectin, in a model of experimental diabetic nephropathy. Diabetic animals were randomly allocated into groups receiving 32 wk of AG or vehicle. Diabetic rats showed increases in CTGF mRNA and protein expression as well as in advanced glycation end-product (AGE) and fibronectin immunostaining, compared with nondiabetic rats. In the diabetic kidney, the increase in CTGF gene and protein expression as well as expression of the extracellular matrix protein fibronectin were prevented by AG. To further explore the relationship between AGEs and mesangial CTGF and fibronectin production, cultured human mesangial cells were exposed in vitro to soluble AGE-BSA and carboxymethyl lysine-BSA, and this led to induction of both CTGF and fibronectin. On the basis of our in vitro findings in mesangial cells linking AGEs to CTGF expression, the known prosclerotic effects of CTGF, and the ability of AG to attenuate mesangial expansion, it is postulated that the antifibrotic effects of AG in this animal model may be partially mediated by CTGF.

Animals↗
PubMed2002

Advanced glycation end products and diabetic complications.

Diabetic complications are major cause of morbidity and mortality in patients with diabetes. While the precise pathogenic mechanism(s) underlying conditions such as diabetic retinopathy, diabetic nephropathy and increased risk of atherosclerosis remain ill-defined, it is clear that hyperglycaemia is a primary factor that initiates and promotes complications. Formation of advanced glycation end products (AGEs) correlate with glycaemic control, and these reactive adducts form on DNA, lipids and proteins where they represent pathophysiological modifications that precipitate dysfunction at a cellular and molecular level. Many of these adducts form rapidly during diabetes and promote progression of a raft of diabetes-related complications. Recent evidence also suggests an important interaction with other pathogenic mechanisms activated within the diabetic milieu. This review outlines the nature of AGE formation in biological systems and highlights accumulative evidence that implicates these adducts in diabetic complications. As more therapeutic agents are developed to inhibit AGE formation or limit their pathogenic influence during chronic diabetes, it is becoming clear that these anti-AGE strategies have an important role to play in the treatment of diabetic patients.

Animals↗
PubMed2002

Effects of low-dose and early versus late perindopril treatment on the progression of severe diabetic nephropathy in (mREN-2)27 rats.

It was previously reported that transgenic (mRen-2)27 rats with streptozotocin-induced diabetes mellitus progressively develop advanced nephropathy in 12 wk. These lesions are largely prevented when the angiotensin-converting enzyme inhibitor perindopril is administered from the time of induction of diabetes mellitus. This study aimed to determine the lowest dose of early perindopril treatment required for substantial improvement of renal function and structure and to investigate whether late intervention prevents or reverses the progression of established renal lesions. At 6 wk of age, female heterozygous Ren-2 rats were randomized to receive either streptozotocin (diabetic) or citrate buffer (control). Rats were gavaged, beginning early after the induction of diabetes mellitus or the administration of control vehicle, with 0, 0.02, 0.2, or 2 mg/kg per d perindopril for 12 wk. A separate group of diabetic Ren-2 rats received late treatment with 2 mg/kg per d perindopril throughout week 8 to week 12, when rats were hypertensive and albuminuric and exhibited increased kidney weight and glomerulosclerotic index (GSI). Among diabetic rats, early 0.02 mg/kg per d perindopril treatment reduced systolic BP, GSI, and renal collagen staining but had no effect on albuminuria or kidney hypertrophy. Early 0.2 or 2 mg/kg per d perindopril treatment further reduced systolic BP, GSI, and renal collagen staining and decreased albuminuria and kidney hypertrophy. Late intervention was as antihypertensive and antialbuminuric as early 0.2 or 2 mg/kg per d perindopril treatment but did not prevent a moderate increase in GSI. In conclusion, early treatment with 0.2 mg/kg per d perindopril was the lowest dosage to largely prevent severe diabetic nephropathy in transgenic Ren-2 rats. Late-onset perindopril treatment of diabetic rats with established nephropathy was as efficacious as early treatment with respect to various renal parameters, such as albuminuria, but was associated with moderate progression of glomerulosclerosis.

Animals↗
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

ALT-946 and aminoguanidine, inhibitors of advanced glycation, improve severe nephropathy in the diabetic transgenic (mREN-2)27 rat.

The severe diabetic nephropathy that develops in the hypertensive transgenic (mRen-2)27 rat with streptozotocin (STZ) diabetes has previously been considered angiotensin II-dependent. Because metabolic pathways are also activated in the diabetic kidney, the present study aimed to determine whether renoprotection could be afforded with inhibitors of advanced glycation end products (AGEs), ALT-946, and aminoguanidine (AG). At 6 weeks of age, nondiabetic control and STZ diabetic Ren-2 rats were randomized to receive vehicle, ALT-946 (1 g/l), or AG (1 g/l) and were studied for 12 weeks. Systolic blood pressure was unchanged with diabetes, ALT-946, or AG. Both kidney weight and glomerular filtration rate were increased with diabetes and unchanged with ALT-946 or AG. ALT-946 and AG equally ameliorated glomerulosclerosis and medullary pathology; however, ALT-946 did reduce cortical tubular degeneration to a greater extent than AG. Albumin excretion rate, which was elevated with diabetes, was reduced with ALT-946 but not AG. AGE immunolabeling was increased in glomeruli and reduced with ALT-946 and AG. These findings indicate that even in the context of renal injury presumed to be primarily blood pressure- and/or angiotensin II-dependent, approaches that interfere with metabolic pathways such as inhibitors of AGE formation can confer renal protection in experimental diabetes.

Amides↗
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↗