Biomedical subjects

Mark E Cooper

Publications and source records attributed to Mark E Cooper.

113 records · Page 7Linked to original sources

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↗

PubMed2002

Treatment for diabetic nephropathy - a review of the recent patent literature.

Diabetic nephropathy is now the leading cause of end-stage renal disease in the Western world. Renal disease develops secondary to long-standing hyperglycemia and hemodynamic alterations, which activate a common pathway that ultimately leads to the renal damage. Current strategies to treat diabetic nephropathy include optimization of glycemic control and treatment of glomerular and systemic hypertension. Although these strategies can slow the progression of proteinuria and decline in renal function, diabetic nephropathy remains a huge clinical problem. It is anticipated that future treatment modalities for preventing and treating diabetic nephropathy will involve drugs that modulate common pathogenetic pathways, possibly acting to inhibit both metabolic and hemodynamically induced forms of renal injury. These include inhibitors of growth factor and cytokine release or action, and inhibitors of intracellular second messengers. Although most of these agents have only been investigated in vitro, in animal experiments, or in relatively short-term human studies, these studies suggest that therapeutic strategies which involve a multifactorial approach may be more successful in the treatment of diabetic kidney disease than drugs which influence only one pathway.

Journal Article↗

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

ACE2, a new regulator of the renin-angiotensin system.

Angiotensin-converting enzyme (ACE) is a zinc metalloproteinase and a key regulator of the renin-angiotensin system (RAS). ACE2 is a newly described enzyme identified in rodents and humans with a more restricted distribution than ACE, and is found mainly in heart and kidney. ACE2 cleaves a single residue from angiotensin I (Ang I) to generate Ang 1-9, and degrades Ang II, the main effector of the RAS, to the vasodilator Ang 1-7. The importance of ACE2 in normal physiology and pathophysiological states is largely unknown. ACE2 might act in a counter-regulatory manner to ACE, modulating the balance between vasoconstrictors and vasodilators within the heart and kidney, and playing a significant role in regulating cardiovascular and renal function.

Angiotensin-Converting Enzyme 2↗

PubMedDate not supplied

Advanced glycation end products and diabetic nephropathy.

Chronic hyperglycemia and oxidative stress in diabetes results in the formation and accumulation advanced glycation end products (AGEs). AGEs have a wide range of chemical, cellular, and tissue effects that contribute to the development of microvascular complications. In particular, AGEs appear to have a key role in the diabetic nephropathy. Their importance as downstream mediators of tissue injury in diabetic kidney disease is demonstrated by animal studies using inhibitors of advanced glycation to retard the development of nephropathy without directly influencing glycemic control. AGE modification of proteins may produce in changes charge, solubility, and conformation leading to molecular dysfunction as well as disrupting interactions with other proteins. AGEs also interact with specific receptors and binding proteins to influence the renal expression of growth factors and cytokines, implicated in the progression of diabetic renal disease. The effects of AGEs appears to be synergistic with other pathogenic pathways in diabetes including oxidative stress, hypertension, and activation of the renin-angiotensin system. Each of these pathways may be activated by AGEs, and each may promote the formation of AGEs in the vicious cycle associated with progressive renal damage. It is likely that therapies that inhibit the formation of AGEs or remove established AGE modifications will form an important component part of future therapy in patients with diabetes, acting in concert with conventional approaches to prevent diabetic renal injury.

Animals↗