Lewis K. Dahl Memorial Lecture

Abstract

identified many of the relationships that underlie our current thinking and focus of research on hypertension. Among the first to establish the interactions between salt and hypertension, the realization that genetic factors played a major role in how the kidney responded to salt loads 1 led to development of the genetically predisposed Dahl salt-sensitive rat. His research, although not specifically directed toward aging, recognized that the effects of high-salt diets were not necessarily immediate. In fact, he suggested that at least one third of the life span was required for salt-induced changes in systolic blood pressure (SBP).I am very grateful for the honor of presenting the Dahl lectureship on work, which, over the past several years, has had aging as the focus. The emphasis has been on the autonomic nervous system, as influenced by the renin-angiotensin system (RAS), specifically, the balance between angiotensin (Ang) II and Ang-(1-7) and the contributions of brain cardiovascular areas to the constellation of changes occurring with advancing age. The overall message derived is that, although the brain RAS plays a major role in all of the age-related changes in cardiovascular and metabolic function, neither the SBP nor the metabolic changes appear to be initiating factors in the activation of the intrarenal RAS or the decline in kidney function during aging ( Figure 1). Differential Regulation of the Circulating and Intrarenal RAS During AgingComponents of the classical circulating RAS, in particular, renin release from the juxtaglomerular cells of the kidney, undergo a decline in older animals. This includes reductions in renal tissue renin mRNA, juxtaglomerular cell renin content, responsiveness of renin release to various challenges, and plasma renin and angiotensin (Ang) II. [2][3][4][5][6][7][8][9] The renal vasoconstrictor responses to exogenously administered Ang II are increased in older animals, 6 perhaps resulting from the reductions in the circulating system. In striking contrast, however, kidney Ang II content increases in older animals. 6This latter finding is not surprising, because all of the components of the RAS are synthesized locally within the kidney, 10 -12 and local production of Ang peptides is regulated independent of the circulating system. 11,13-16 Thus, whereas the juxtaglomerular cell renin and its release into the circulation are considered representative of the circulating/hormonal RAS, renal tissue content, tubular fluid, or urinary RAS components are considered representative of the intrarenal RAS.The concept of differential regulation of the circulating and intrarenal or other tissue RAS is not new.12 One possibility for these differences relate to the increase in SBP. An increase in arterial pressure during aging may lead to a baromediated reduction in renin release from the kidney, contributing to the decline in the circulating RAS. In contrast, for the intrarenal system, there is evidence that the regulation of tubular renin may be opposite to or at least different fro...

Review:Novel roles of nuclear angiotensin receptors and signaling mechanisms

“…There is strong evidence that ACE inhibitors or AT 1 receptor antagonists have a profound impact on the treatment of cardiovascular disease. Emerging data suggest that the RAS may influence the course of other pathologies, including cancer, diabetes, pulmonary injury and aging (25,26). Indeed, AT 1 receptor knockout mice exhibit a significant increase in life span when maintained on a normal chow/caloric diet, which supports earlier studies on the protective effects of ACE inhibitors in aging rats (2,26,28,33).…”

“…Emerging data suggest that the RAS may influence the course of other pathologies, including cancer, diabetes, pulmonary injury and aging (25,26). Indeed, AT 1 receptor knockout mice exhibit a significant increase in life span when maintained on a normal chow/caloric diet, which supports earlier studies on the protective effects of ACE inhibitors in aging rats (2,26,28,33). Our studies in older adult sheep also revealed evidence for an altered balance in the nuclear expression of ANG receptors, as well as the functional responses of the ANG II-AT 1 receptor axis (40).…”

Mechanism of Ang II involvement in activation of NF-κB through phosphorylation of p65 during aging

“…Recent studies have suggested their potential role in the activation of inflammatory mechanisms associated with age-related vascular and renal damage. For one thing, Ang II signaling increases with aging (Basso et al 2005;Diz and Lewis 2008). For another, suppression of Ang II signaling attenuates the development of age-related vascular diseases.…”

“…However, recent studies have shown that it is also a potent mediator in the activation of inflammatory mechanisms during age-related vascular and renal disease (Basso et al 2005;Diz and Lewis 2008). The use of Ang II antagonists in the treatment of these agerelated diseases provides strong support for its proinflammatory role (de Cavanagh et al 2003(de Cavanagh et al , 2004.…”

Angiotensin II Type 1 (AT1) Receptor Deficiency Halts the Progression of Age-Related Atherosclerosis in Hypercholesterolemia: Molecular Link between the AT1 Receptor and Hypercholesterolemia

“…Aging is also associated with activation of local tissue RAS and systemic RAS blockade prevents other age-related changes; this strongly suggests that mechanisms involving the blockade of local-tissue RAS contribute to the protective effects of systemic RAS blockade during aging (13). Importantly, other components of the local RAS in vessel walls such as angiotensin-converting enzyme (ACE) are also upregulated during atherosclerosis, and a high abundance of Ang II has been shown in atherosclerotic plaques as well as in hypercholesterolemia (3,14,15).…”