While there have been reports on changes in the renin-angiotensin system and angiotensin II (AT) receptors in diabetes, there is no agreement on the nature of these changes. This study has characterised specific AT receptors in the heart, kidney, liver and adrenal glands of the streptozotocin (STZ)-diabetic rat using radioligand binding studies with the radioligand 125I-[Sar1, Ile8]-angiotensin II. Left ventricular AT receptor density increased by 135% 4 weeks after treatment and by 206% 12 weeks after treatment; in the liver, AT receptor density increased by 476% (4 weeks) and 263% (12 weeks) and in the adrenal gland by 236% (4 weeks) and 109% (12 weeks). In contrast, renal AT receptor density decreased by 49% (4 weeks) and 36% (12 weeks). Competition-displacement assays with losartan, an AT1-selective ligand, showed that the proportion of AT receptor subtypes remained unchanged. STZ treatment decreased plasma angiotensinogen by 72% (4 weeks) and 67% (12 weeks) and increased plasma renin concentration after 12 weeks; plasma renin activity and aldosterone concentrations remained unchanged. Treatment with human insulin (5 U/day) attenuated changes in plasma angiotensinogen and AT receptor density except in the left ventricle. We conclude that there are major changes in AT receptors in the STZ-diabetic rat that are tissue-specific and time-dependent. Plasma angiotensinogen and renin secretion change in directions that result in the maintenance of plasma renin activity and aldosterone concentration.

A recent report from the American Heart Association in 2018 shows that over 103 million American adults have hypertension. The angiotensin-converting enzyme (ACE) (EC 3.4.15.1) is a dipeptidyl carboxylase that, when inhibited, can reduce blood pressure through the renin-angiotensin system. ACE inhibitors are used as a first-line medication to be prescribed to treat hypertension, chronic kidney disease, heart failure among others. It has been suggested that ACE inhibitors can reduce the symptoms in mouse models. Despite the benefits of ACE inhibitors, previous studies also have suggested that alterations in the ACE gene are risk factors for Alzheimer’s disease (AD) and other neurological diseases. In mice, overexpression of ACE in the brain reduces symptoms of the AD-model systems. Thus, we find opposing effects of ACE on health. To clarify the effects, we dissect the functions of ACE as follows: (1) angiotensin-converting enzyme that hydrolyzes angiotensin I to make angiotensin II in the renin-angiotensin system; (2) amyloid-degrading enzyme that can hydrolyze beta-amyloid and reduce amyloid toxicity. The efficacy of the ACE inhibitors is well established in humans, while the knowledge specific to AD remains to be open for further research. We provide an overview of ACE and inhibitors that link a wide variety of age-related comorbidities from hypertension to Alzheimer’s disease to aging. ACE also serves as an example of the middle-life crisis theory that assumes deleterious events during the midlife, leading to age-related later events.

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PurposeChronic ethanol (EtOH) ingestion increases the incidence of the acute respiratory distress syndrome and causes oxidative stress and cellular dysfunction in the lung. The mechanisms of EtOH-induced oxidative stress in the lung remain to be defined. We sought to determine if chronic EtOH ingestion alters the expression of lung NADPH oxidase, a major enzymatic source of superoxide generation, in an in vivo rat model of chronic EtOH ingestion.MethodsMale Sprague-Dawley rats were fed liquid diets containing EtOH (36% of calories) or an isocaloric diet substituting maltin-dextrin for EtOH (control) with or without the angiotensin-converting enzyme (ACE) inhibitor lisinopril for 6 weeks. Prior to sacrifice, blood pressure was monitored for 15-20 minutes. After sacrifice, lung frozen sections were stained with dihydroethidium (DHE) to detect superoxide production. Expression of specific components of the renin-angiotensin system (RAS) and specific NADPH oxidase components were then examined in lung homogenates.ResultsChronic EtOH ingestion in the rat had no significant effect on blood pressure but increased superoxide formation in lung parenchyma measured as DHE fluorescence, an effect inhibited by lisinopril. Chronic EtOH ingestion failed to increase lung ACE expression, but increased angiotensinogen, angiotensin II type 1 (AT1) and type 2 (AT2) receptor expression. Chronic EtOH ingestion also increased expression of the NADPH oxidase subunit, gp91phox, an effect inhibited by lisinopril.ConclusionsThese results indicate that chronic EtOH ingestion alters superoxide production and specific NADPH oxidase subunit expression in the lung by a RAS-dependent pathway. These findings provide new insights into mechanisms by which EtOH causes oxidative stress in the lung.

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