The production and action of Ang II is regulated at multiple levels, including the availability of angiotensinogen, levels and activities of angiotensin-processing enzymes, angiotensin receptor isotype expression, and postreceptor signaling (Fig. 1). Although quantitation of Ang II levels would provide a direct measure of extracellular RAS activation, these measurements are complicated by the rapid degradation of this peptide (46,47) and its tissue-specific production (26,27,48). Reports on the effects of diabetes on plasma and tissues Ang II levels are controversial. Studies of streptozotocin (STZ)-induced diabetes in rats have reported no effect of diabetes on Ang II levels in plasma, kidney, aorta, and heart (49), reduced renal Ang II but normal levels in plasma Ang II (50), and decreased plasma Ang II in diabetes (51). Similar controversies appear for the effects of diabetes on changes in upstream components of the RAS. For example, recent studies have reported that plasma renin is normal (52) or reduced (53) in diabetes. Similarly, in experimental animal models of diabetes, plasma renin has been reported to be normal (54,55) or reduced (56-60) in STZ-induced diabetic rats, and reduced in Zucker diabetic fatty rats (61). In addition to discrepancies on the changes of plasma renin levels, the significance of these changes is unclear. Although low-plasma renin may indicate suppression of the RAS it may also reflect autoregulation as a result of its renal activation. Ang II is a potent inhibitor of renal renin production (62). Thus, low-plasma renin in diabetes may be the result, in part, of an increase in renal Ang II action. Increased renal perfusion response to AT1 antagonism suggests that increased intrarenal Ang II production and action may occur in type 2 diabetes even though plasma renin activity is reduced
(53). Acute hyperglycemia increases AGT expression in both liver and adipose tissue (63), suggesting that diabetes may increase AGT substrate availability. High glucose increases Ang II release from cardiomyocytes (64) and ATI receptor expression in VSMC (65), suggesting that hyperglycemia may locally upregulate the RAS in vascular tissues.
Additional factors, including parasympathetic nervous activation, hypovolemia, and sodium resorption, may affect the regulation of the RAS in diabetes. Although changes in individual components of this system may affect overall RAS activity, interpretation of these changes is limited by the potential of downstream modulation of Ang II action or stability. Moreover, because the RAS appears to be locally regulated, it may not be appropriate to extrapolate changes in RAS component levels beyond the specific tissues and conditions studied.
Diabetes may increase RAS action in the vasculature by increasing its sensitivity to the effects of Ang II. Both increased systemic and renal sensitivity to the pressor effects of Ang II have been reported in diabetes (66,67), and in diabetic patients with microvascular disease (68,69). In cultured VSMCs, elevating extracellular glucose from 5 ml to 25 mM has been shown to exert additive and/or potentiating effects on Ang II-induced activation of the extracellular signal-regulated kinase (ERK) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways (70,71). The effects of diabetes on enhancing Ang II action could be mediated by increases in ATI receptor expression, changes in postreceptor signaling mechanisms, and/or a reduction in cellular signals that suppress ATI responses. STZ-induced diabetes upregulates ATI receptor levels in the heart of rats (55,56) and within atherosclerotic lesions in apo-E deficient mice (72). Elevated concentrations of extracellular glucose increase ATI receptor expression in cultured VSMC (65). Although these increases in ATI expression may affect Ang II sensitivity and/or maximal effect in these vascular target tissues, physiological relevance of these changes in receptor levels as a rate limiting determinant in Ang II action have not yet been demonstrated. Additionally, the synergistic effects of Ang II and high glucose could be mediated by the convergence of these agonists on signaling pathways, such as protein kinase C and reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (73).
A number of factors have been shown to attenuate ATI signaling and action in the vasculature. The angiotensin AT2 receptor has been shown to inhibit or counteract many of the trophic effects of ATI (41). Thus, the relative expression of ATI and AT2 receptors subtypes may be an important determinant in modulating the actions of the Ang II/AT1 signaling pathway. Additionally, other vascular hormones systems induce signals that oppose or interfere with ATI signaling. Our laboratory and others have shown that cyclic guanosine monophosphate-coupled hormones, including nitric oxide (NO) and natriuretic factors, inhibit Ang II-induced plasminogen activator inhibitor-1 (PAI-1) gene expression in both vascular endothelial cells and VSMC (74,75). NO donors have been shown to reduce Ang II-stimulated growth, migration, and gene expression in a variety of cultured vascular cells (76-78). A role of NO in suppressing ATI action is particularly intriguing because impaired NO action is a component of endothelial dysfunction in diabetes (79,80). Thus NO generated from the endothelium may normally suppress or oppose ATI action and the impairment of this endothelium function in diabetes may lead to the apparent sensitization of the Ang II/AT1 pathway.
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