Mathematical Modelling of the Intrarenal Renin Angiotensin System in Hypertension

Abstract

Hypertension is the leading cause of cardiovascular disease and premature death world-wide. It is a highly multi-factorial disease associated with multiple risk factors and patho-physiological changes, including impaired kidney function and an over-active renin angiotensin system (RAS). Many hypertensive actions of angiotensin II (Ang II), the primary bio-active product of the RAS, are mediated within the kidney; an organ that also expresses and independently regulates all RAS constituents. The interconnected nature of the systems involved makes it difficult, and in many cases impossible, to identify their individual contributions to the observed pathology in vivo. Thus, the goal of this thesis is to investigate the role of the local intrarenal RAS in the pathogenesis and progression of hypertension in silico. In particular, we first developed a computational model of the intrarenal and systemic RASs in isolation to unravel the mechanisms that mediate the former's over-activity in Ang II infused hypertensive rats (an experimental model of hypertension). Then, by extending the model to include a pharmacokinetic representation of an angiotensin receptor blocker (ARB), a common RAS-modulating anti-hypertensive therapy, we examined the impact of this class of medication on the kidney. Lastly, by coupling our model to one of whole-body blood pressure regulation in the rat and creating the first model of long-term blood pressure regulation that considers a intrarenal RAS, we zoomed back out to determine how the aforementioned effects actually contribute to blood pressure dis-regulation.

Our results suggest that Ang II accumulates in the kidney during the development of Ang II-induced hypertension because of enhanced angiotensin type 1 receptor (AT1R)-mediated uptake of circulating Ang II, which is facilitated by positive feedback on intrarenal AT1R expression. By inhibiting this feedback loop, and others inherent to the intrarenal RAS, ARBs effectively prevent intrarenal Ang II levels from increasing. However, it is rather by restricting Ang II to extracellular regions of the kidney that ARBs effectively restore normotension. In the absence of treatment, rising concentrations of cell-associated Ang II act to increase blood pressure by stimulating sodium reabsorption along the nephron. The timing of this response also affects blood pressure dynamics. Indeed, slow-pressor hypertension is a consequence of systemic and intrarenal RAS decoupling: The progressive accumulation of Ang II in the kidney permits the sequential activation of sodium reabsorption by aldosterone, then Ang II. Our results shed light on the functional importance of the intrarenal RAS in hypertension induced by Ang II infusion, and thus clinical hypertension associated with an over-active RAS.