Suzette Y. Osei

Effect of Angiotensin II Antagonist Eprosartan on Hyperglycemia-Induced Activation of Intrarenal Renin-Angiotensin System in Healthy Humans

We have previously reported that hyperglycemia in healthy human subjects increased the renal vasodilator response to the angiotensin-converting enzyme inhibitor captopril. This observation raised intriguing possibilities relevant to the pathogenesis of nephropathy in patients with diabetes mellitus. To ascertain whether the effect of captopril was indeed mediated by a reduction in angiotensin II (Ang II) formation, we performed another study in which an Ang II antagonist, eprosartan, was used in place of captopril. Nine healthy subjects were studied in high sodium balance (ie, sodium intake 200 mmol/d). On the first day, the subjects received 600 mg eprosartan orally, and renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured. Glucose was infused intravenously on the second and third study days to increase plasma glucose to a level below the threshold for glycosuria ( approximately 8.8 mmol/L). Eprosartan at a dose of 600 mg or placebo was administered randomly on the second or third study day 1 hour after initiation of glucose infusion. RPF increased (by 76+/-7 mL. min(-1). 1.73 m(-2), P<0.01) in response to sustained moderate hyperglycemia and then increased further (by 147+/-15 mL. min(-1). 1. 73 m(-2), P<0.01) when eprosartan was administered during hyperglycemia. Eprosartan, conversely, did not affect RPF and GFR in normoglycemic subjects. GFR was not affected by either hyperglycemia or eprosartan. Neither plasma renin activity nor plasma Ang II concentration changed during hyperglycemia, suggesting that the hormonal responses responsible for the enhanced renal vasodilator response to eprosartan occurred within the kidney. The enhancement of the renal vasodilator effect of eprosartan during hyperglycemia is consistent with activation of the intrarenal renin-angiotensin system.

Hyperglycemia and angiotensin-mediated control of the renal circulation in healthy humans

Type 1 and type 2 diabetics have an enhanced renal vasodilator response to angiotensin-converting enzyme (ACE) inhibition despite suppressed plasma renin activity (PRA), indicating possible activation of the intrarenal renin angiotensin system. To investigate the role of hyperglycemia, we evaluated the renal hemodynamic response to ACE inhibition in 9 healthy subjects in high-salt balance after steady-state hyperglycemia (8.4+/-1 mmol/L) was achieved via intravenous glucose administration. Renal plasma flow (RPF) and glomerular filtration rate (GFR) responses to captopril and to angiotensin II (Ang II) were measured as paraminohippuric acid and inulin clearances. Hyperglycemia produced a significant increase in RPF of 117 mL. min-1. 1.73 m-2 after 90 minutes but not GFR. Administration of captopril at a dose of 25 mg during glucose infusion led to an increase in RPF of 173+/-24 mL. min-1. 1.73 m-2 (P<0.01) but did not significantly change RPF in the absence of hyperglycemia (7+/-21 mL. min-1. 1.73 m-2). Captopril did not alter GFR in the presence or absence of hyperglycemia. Ang II infusion during hyperglycemia decreased RPF by 45+/-16 mL. min-1. 1. 73 m-2, and this was significantly enhanced by captopril (-98+/-26 mL. min-1. 1.73 m-2, P<0.05). In contrast, there was no enhancement of the vasoconstrictor response to Ang II in the absence of hyperglycemia. PRA did not change with hyperglycemia. Enhancement of renal vasodilation during hyperglycemia by captopril without alteration of PRA suggests activation of the intrarenal renin angiotensin system.

Type 2 diabetes, obesity, and the renal response to blocking the renin system with irbesartan

Aim Our recent studies revealed a striking but variable enhancement of renal vasodilator responses to blockers of the renin‐angiotensin system in subjects with diabetes mellitus, possibly reflecting the level of intrarenal activation of the renin‐angiotensin system, and thus a risk of nephropathy. As obesity is a common finding in diabetic individuals, and obesity has been linked to an increase in plasma angiotensinogen levels, we enrolled diabetic subjects with a wide range of body mass index (BMI) for this study.

The endocrine role of adipose tissue: Focus on adiponectin and resistin

Purpose of reviewIn addition to storing energy, adipose tissue secretes various proteins including leptin, adiponectin, resistin, cytokines, coagulation and vasoactive peptides. The levels of these ‘adipokines’ are related to adiposity; hence, they could provide molecular mechanisms for diabetes, dyslipidemia, atherosclerosis and other complications of obesity. Recent findingsLeptin inhibits feeding by binding to the long leptin receptor (LRb) in the brain, leading to activation of the JAK-STAT pathway. The leptin signal is terminated through induction of SOCS3 and PTP1B activity. The importance of these molecules has been confirmed in knockout mice. Ablation of LRb or STAT3 in neurons causes hyperphagia, obesity and neuroendocrine deficits, while the loss of SOCS3 or PTP1B prevents obesity. Adiponectin has also attracted attention because it is reduced in obesity and diabetic humans and animals. Treatment with adiponectin improves insulin sensitivity, decreases lipids by enhancing oxidation, and protects against vascular inflammation and atherosclerosis. Adiponectin is increased by thiazolidinediones and likely mediates the antidiabetic effects of these drugs. Resistin exerts an opposite effect to adiponectin by inhibiting insulin action in rodents; however, its role in humans is less certain. SummaryIdentification of the key molecular pathways underlying the actions of adipocyte hormones provides new insights into their roles in health and disease. Specific targets of adipocyte hormones could potentially benefit the diagnosis and treatment of obesity and other metabolic diseases.

Hyperglycaemia-induced intrarenal RAS activation: the contribution of metabolic pathways

Hyperglycaemia-induced activation of the renin-angiotensin system (RAS) has been observed in normal and diabetic humans. Our main objective was to determine whether the mechanism involved a physical or metabolic effect of glucose. First, Sprague-Dawley rats of the CD strain were given sequential intravenous (i.v.) doses of 0.01, 0.1, 1.0, and 3.0 mg/kg candesartan 30 minutes apart, in the presence of a continuous i.v. infusion of dextrose 20% in water (D20W). The 0.1 mg/kg dose produced a maximal renal blood flow (RBF) response and was used thereafter. Another set of animals then received an infusion of either normal saline (NS), dextrose 5% in water (D5W) or dextrose 20% in water (D20W) for 2 hours, followed by candesartan 0.1 mg/kg i.v. Finally, the response to candesartan 0.1 mg/kg i.v. during D20W infusion was compared with that during infusion of 2-deoxyglucose (2DG), a glucose analogue that competitively inhibits the glycolytic enzyme, hexokinase. RBF (electromagnetic flowmeter), blood pressure (BP), blood glucose, and urine glucose were monitored. There was no significant RBF response to candesartan on either NS (6.01±0.48 to 6.20±0.49 ml/minute/g kidney; p=0.216) or D5W (7.63±1.20 to 7.58±1.39 ml/minute/g kidney; p=0.965), whereas there was a significant response to D20W (6.64±0.59 to 7.46±0.67 ml/minute/g kidney; p=0.002). The RBF response was significantly enhanced by D20W compared with 2DG (change in RBF: 0.82±0.22 vs. -0.04±0.26; p=0.05), despite similar BP, blood glucose, and urine glucose. Glucose acts, at least in part, through intracellular utilisation to induce RAS activation, as manifested by an enhanced renal vascular response to an angiotensin II antagonist.

Salt intake and non-ACE pathways for intrarenal angiotensin II generation in man

Angiotensin-converting enzyme (ACE) plays a crucial role in the generation of angiotensin II (Ang II) via conversion from angiotensin I (Ang I). There has been substantial recent interest in non-ACE pathways of Ang II generation in the heart, large arteries, and the kidney. In the case of the human kidney, studied when in balance on a low-salt diet, the renal haemodynamic response to Ang II antagonists substantially exceeds the renal response to ACE inhibitors (ACE-I), suggesting that about 30—40% of Ang II-generation occurs via non-ACE pathways. In this study, we examined the relative contribution of non-ACE pathways, by comparing the response to candesartan and to captopril at the top of the dose-response in normal humans when in balance on a low-salt, as well as a high-salt, diet. As anticipated on a low-salt diet, the increase in renal plasma flow (RPF) in response to candesartan (165±14 mL/min/1.73m 2) significantly exceeded the response to captopril (118±12 mL/min/1.73m 2; p<0.01). In subjects studied on a high-salt diet, the response to candesartan (97±20 mL/min/1.73m2) also significantly exceeded the response to captopril on the same diet (30±15 mL/min/1.73m2; p<0.01). This remarkable response to candesartan in subjects on a high-salt diet, when compared with the response to captopril, suggests that non-ACE-dependent Ang II generation was influenced less than the classical renal pathway with an increase in salt intake, so that the percentage of Ang II generated via the non-ACE pathway rose to the 60—70% range.

Neuroendocrine regulation of appetite and energy balance

The current understanding of appetite and body weight regulation has benefited greatly from the discovery of leptin and advances in the molecular genetics of obesity. Leptin acts as an afferent signal in the brain to suppress appetite and increase energy expenditure. Failure of the leptin feedback system culminates in obesity, diabetes, and a variety of neuroendocrine abnormalities. Energy homeostasis is also influenced by insulin, glucocorticoids, sex steroids, and proinflammatory cytokines. These circulating factors regulate feeding behavior and body weight mainly through the expression of neurotransmitters and peptides in the hypothalamus and various central nervous system regions. By studying the interactions between peripheral signals and central neuronal pathways, researchers hope to gain a better understanding of the pathogenesis of eating disorders, obesity, and associated metabolic disorders.

Renal hemodynamic and hormonal responses to the angiotensin II antagonist, candesartan: the angiotensin II-renin short feedback loop.

The development of very specific blockers for the angiotensin II type 1 (AT1) receptor made it possible to examine the contribution of angiotensin II to normal control mechanisms and disease with a specificity beyond what ACE inhibitors could provide. In the present study, we explored the contribution of angiotensin II to 2 renal mechanisms: renal hemodynamics and the short feedback loop, in which angiotensin II acts as a determinant of renin release. To make that comparison, we studied healthy volunteers in balance on a 10-mmol sodium intake to activate the renin system. Our goal was to compare the relation between the dose of candesartan, an AT1 receptor blocker, and the renal hemodynamic and hormonal responses. A second goal was to ascertain the relation between time after candesartan administration and the peak response. Twelve healthy subjects (mean age 33±2.3 years) in low-sodium balance were administered candesartan in 4-, 8-, 16-, and 32-mg doses. Candesartan produced a dose-related increase in renal plasma flow, with the maximum vasodilator response at 16 mg (142±13 mL · min−1 · 1.73 m−2) occurring during the first 4 hours after the dose. Likewise, candesartan caused a dose-related rise in plasma renin activity, with 32 mg as the dose producing the greatest response at 4 and 24 hours after administration. The peak plasma renin activity achieved in this study (15.3±1.6 ng · L−1 · s−1; 55.0±5.6 ng angiotensin I · mL−1 · h−1) was found at the 4- to 8-hour interval after dosing in a subset of subjects (n=5) who received the 16-mg dose 4 hours earlier than the other subjects. On the basis of the difference in the relation between dose and response and the relationship between time after drug administration and response, the determinants of the renal hemodynamic and hormonal response can be said to differ. The remarkable rise in plasma renin activity after candesartan is substantially larger than that in earlier studies with ACE inhibition, providing additional evidence for non–ACE-dependent angiotensin II generation in the kidney.

Sickle Cell Disease and NO

A wide spectrum of functional and anatomical abnormalities occurs in the kidneys of patients with sickle cell disease (SS). In children and young adults, with either SS or SA - sickle cell trait disease, there is a renal concentrating defect which is reversible with blood transfusion [1]. Beyond the age of 15 however, blood transfusions no longer correct the defect. Occlusion of the vasa recta by sickled red blood cells (RBC), leading to tubular atrophy, interstitial scarring, and microinfarcts is thought to underlie the progressive nature of the concentrating defect [12]. More subtle functional disturbances in tubular transport are common and include the inability to sustain a maximum [H+] gradient and impaired K* secretion unrelated to the renin/aldosterone axis [35]. The transport defects do not usually translate into clinically apparent electrolyte disturbances unless some intervening event tips the scales, such as sepsis, excess dietary potassium intake, or a potassium-sparing drug is prescribed [6].