The tissue renin-angiotensin-aldosterone system in diabetes mellitus

Abstract

Diabetes is associated with an inordinate burden of cardiovascular and renal disease, which is expected to accelerate during the next few decades. The relationship between the renin-angiotensin system (RAS) and diabetic macrovascular and microvascular disease is well established. The contribution of the tissue RAS in disease pathogenesis has recently been the focus of much interest, and has prompted investigators to explore the use of high-dose RAS inhibition with monotherapy or combination therapy to provide a more complete blockade of the actions of angiotensin II, beyond lowering blood pressure. There is now evidence to support this approach to maximize cardiovascular and renal protection. Optimal dosing strategies remain uncertain, but tissue specificity does not appear to be important if the doses of angiotensin-converting enzyme-I and angiotensin-receptor binders are high enough. The purpose of this review is to highlight our current understanding of the role of the tissue RAS in the pathogenesis of diabetic end-organ damage and ongoing strategies to interfere pharmacologically.

Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension

“…Inhibition of the renin system with ACE-inhibitors or angiotensin receptor blockers (ARBs) is an attractive therapeutic approach for this patient group because increased tissue renin system activity may be a major factor in the development of organ damage in diabetes. 5,6 Indeed, clinical trials have shown that ACE-inhibitor or ARB treatment slows the progression of renal disease in patients with type 2 diabetes and hypertension. 7,8 ACE-inhibitors and ARBs inhibit negative feedback mechanisms, resulting in a reactive increase in plasma renin activity (PRA; the capacity of renin to convert angiotensinogen to angiotensin [Ang] I) that may lead to increased generation of Ang II.…”

Diabetic Brain Damage in Hypertension

“…9,10 In addition, animal studies have shown that ARBs enable endogenous angiotensin II to stimulate neuronal regeneration via activation of AT 2 receptors. 11 Although the relationship between the tissue RAS and diabetic macrovascular and microvascular disease is well established, 12 the effects of ARBs on cerebral metabolism and hemodynamics have not been fully investigated.…”

Chronopharmacology of Angiotensin II–receptor Blockers in Stroke-Prone Spontaneously Hypertensive Rats

“…Elevated endogenous AII is believed to cause organ damage (32). For example, Takai et al reported that although BP was not lowered, trandolapril reduced tissue ACE activity and prolonged survival in SHRSP (33).…”