Interaction of the renal amylin and renin-angiotensin systems in animal models of diabetes and hypertension.

Abstract

The range of known actions of amylin are reviewed together with the proposal that an important role for amylin may be the hormonal integration of diverse physiological systems activated with feeding. Major targets for the action of amylin are found within the kidney. Components of the amylin system (AS) have been shown to influence the activity of components of the renin-angiotensin system (RAS), and vice versa, in normal, hypertensive and diabetic models. For instance, amylin injected into humans and rats elicits a rapid rise in plasma renin activity. Furthermore, in two models of hypertension (the spontaneously hypertensive rat (SHR) and the model with subtotal nephrectomy (STNx)), the density of amylin-binding sites in the renal cortex associated with the proximal tubules, was associated with elevation of blood pressure. In normotensive controls and in the STNx model, but not in the SHR model, treatment with angiotensin-converting enzyme (ACE) inhibitors reduced blood pressure and the density of amylin binding in the renal cortex. In Sprague-Dawley rats, angiotensin II (Ang II) infusion was associated with increased density of amylin-binding sites as well as elevated blood pressure. Thus, there appears to be a direct relationship between the activity of Ang II and the binding sites for amylin in the renal cortex. From these studies it has been postulated that the activation of the AS in the kidney may play a role in the genesis and/or development of hypertension in certain contexts. The transient expression of amylin mRNA has been detected perinatally, using in situ hybridization, in the subnephrogenic zone of the metanephros and is associated with proximal tubules of the developing nephron. These cells situated close to the glomeruli, represent a subset of brush border epithelial cells. Amylin immunoreactivity (IR) is also found in these cells and colocalizes with angiotensinogen IR. Thus a second important role for amylin is described in which it plays a role as a growth factor in the developing kidney and in renal regrowth in the adult kidney. In a model of IDDM (streptozotocin diabetes), amylin and angiotensinogen IR are both restricted to a subset of brush border epithelial cells close to glomeruli which, in the developing kidney, expressed amylin mRNA. Thus in this IDDM model, we hypothesize that amylin mRNA transcription which is normally downregulated in the adult, is upregulated in this subset of these brush border epithelial cells, and that it stimulates the activity of a local RAS by an intracellular mechanism, leading to the biosynthesis of Ang II. It remains to be determined that if amylin is playing a role in stimulating local Ang II production at these sites, this provides a mechanism for activation of TGF-beta, ultimately leading to interstitial fibrosis.