The Renin–Angiotensin–Aldosterone System and the Kidney

1

Introduction

The relationship between the renin–angiotensin–aldosterone system (RAAS) and its modulation of kidney function has been present for almost a century. It dates back to when renin was first described in the late 1800s and integrated into renal physiology with the experiments of Harry Goldblatt. Studies over the past four decades have further crystallized our knowledge of the cellular and molecular role of this system on kidney function. Acting both as an endocrine organ and a target organ, the kidney profoundly affects and is affected by the RAAS, resulting in a variety of physiologic and pathophysiologic effects with wide-reaching treatment implications in diseases as diverse as diabetes and congenital abnormalities. This chapter will primarily discuss the renin–angiotensin system (RAS) as aldosterone is discussed in detail in Chapter 23, Chapter 24, Chapter 25, Chapter 26, Chapter 27 .

2

Historical Background

The prominent vasopressor actions of this system first led to the discovery of the RAS. In the late 19th century, Tigerstedt and Bergman, having observed the association between kidney disease and hypertension, injected kidney extracts into rabbits and found elevated blood pressure in these animals. They theorized that a soluble protein contained within the kidney acted directly as a vasopressor and named this compound renin. Numerous unsuccessful models of renal-injury hypertension followed until 1934, when Harry Goldblatt developed his model of renovascular hypertension. By placing silver clamps over canine renal arteries, Goldblatt demonstrated a sustained increase in blood pressure. Clamps over other large, nonrenal arteries did not elicit a similar blood pressure response, and so, like Tigerstedt and Bergman, Goldblatt suggested that renal ischemia caused the secretion of a compound which triggers vasoconstriction.

The nature of renin became clear due to the work of many researchers, most prominently by two laboratories under the direction of Eduardo Braun-Menendez and Irvine Page. Both groups ultimately demonstrated that renin was secreted by the kidney but was in fact not directly responsible for vasoconstriction. Instead, a blood component was necessary which was enzymatically cleaved by renin to generate an active molecule. This active peptide was named hypertensin by Braun-Menendez and angiotonin by Page before the groups ultimately compromised and dubbed it “angiotensin.” Leonard Skeggs et al. would later discover that this protein actually existed in two forms, with angiotensin-converting enzyme (ACE) converting angiotensin I (AI) into its active form, angiotensin II (AII).

3

Overview of the Renin–Angiotensin System Pathway

The combined efforts of these investigators defined the framework for the renin–angiotensin pathway, upon which numerous investigators have built and established a complex series of biochemical pathways and ligand–receptor interactions to form our current understanding of the RAS ( Fig. 2.1 ).

Forming the backbone of this system is the well-known cascade by which renin triggers angiotensinogen (ANG) conversion into AI and ultimately AII. In the rate-limiting step of this pathway, renin, an aspartyl protease, is secreted by the juxtaglomerular cells in the kidney and cleaves the hepatically secreted glycoprotein ANG into AI. AI is a biologically inactive decapeptide that is rapidly metabolized by ACE, found in many tissues, but particularly in the lung, into the biologically active octapeptide, AII. In addition to its many actions that exert a direct effect on renal hemodynamics or tubule function, AII acts to stimulate the production of aldosterone by the zona glomerulosa of the adrenal gland.

Metabolites of ANG further downstream have also been shown to have biologic activity. Cleaving the two terminal amino acids from AII creates angiotensin IV (AIV), which binds to type 4 angiotensin receptors (AT ₄ ). AIV activation of AT ₄ promotes natriuresis, presumably mediated by decreased proximal and distal tubule sodium reabsorption.

The action of endopeptidases on either AI or AII can result in the formation of another active metabolite, angiotensin 1–7 (A1–7). A1–7 acts as a vasodilator in the vasculature via production of nitric oxide, prostaglandins, or other chemokines. Concentrations of A1–7 are similar to AII levels in the kidney, and its role in the kidney is still evolving, with data demonstrating potential antihypertensive effects, both diuretic and antidiuretic effects and a potential relationship to repair after injury. Interestingly, gender differences may play a role on A1–7 expression and action.

In some cases, the circulating AII and other active metabolites may not be the key determinant in the renal response to the RAS. Instead, a local renal RAS appears to act in an autocrine and paracrine fashion. Renin, ANG, and ACE have been found in the kidney, as well as various angiotensin receptors and Mas, the receptor for A1–7. Proximal tubule cells appear to produce both renin and ANG and secrete them into the tubule lumen. ACE is present in the brush border of the proximal tubule and likely converts AI into AII, as AII levels in the renal interstitium are some 1000 times higher than the blood. In addition to its effects on renal hemodynamics and tubular transport, AII appears to stimulate proximal tubule production of ANG, acting as a positive feedback loop.

4

Physiologic Effects of Renin–Angiotensin System

The effectors and receptors that make up the RAS mediate a vast number of nonrenal physiologic effects throughout the body, notably in the heart, vasculature, brain, lung, and adrenal gland. Within the kidney, the RAS regulates renal hemodynamics, tubular transport, inflammation, and cell growth and differentiation.

4.1

Renin–Angiotensin System and Renal Hemodynamics

Perhaps the most well-known effect of the RAS in the kidney is the action of AII on the renal vasculature. AII functions as a vasoconstrictor in interlobular artery and both the afferent and efferent glomerular arterioles, but with greater potency in the efferent arteriole. These actions elevate the intraglomerular capillary pressure. AII also constricts the glomerular mesangium and enhances the afferent arteriole response to tubuloglomerular feedback (TGF). These effects have contrasting effects on glomerular filtration rate (GFR). The preferential vasoconstriction of the efferent arteriole and resulting increase in glomerular hydrostatic pressure tends to preserve GFR under states of RAS activation, but mesangial, afferent, and systemic vasoconstriction lower renal blood flow and therefore decrease GFR. The net result is generally an increase in filtration fraction, owing to a relatively smaller decrease in GFR compared to renal blood flow.

The differential vasoconstrictor activity responsible for this phenomenon is best explained by the interaction of AII-mediated vasoconstriction with various local mediators of vasodilation stimulated by AII ( Fig. 2.2 ). The rationale for this hypothesis comes from contrasting results between in vivo and in vitro vasoconstrictor studies. Microperfusion studies have demonstrated a 100-fold greater sensitivity for AII to elicit a vasoconstrictor response in the efferent versus afferent arteriole. In vitro studies, however, failed to show a difference in vasoconstrictor sensitivity, suggesting that the production of other local factors stimulated by AII may contribute to the differential response. Among these are vasodilatory prostaglandins secreted by the glomerulus in response to AII. Experimental inhibition of prostaglandin synthesis with indomethacin enhances afferent and efferent arteriole vasoconstriction by AII, with afferent arteriolar response to AII increasing 10-fold. In addition, AT ₂ receptor activation in the afferent arteriole may play a significant role. AT ₂ receptor blockade has been experimentally shown to augment AII-induced vasoconstriction as well as inhibit AII-mediated vasodilation in preconstricted vessels. As AT ₂ stimulation has been linked to nitric oxide production, it is likely that nitric oxide mediates this effect.

The phenomenon of renal autoregulation of blood flow is essential to normal kidney function and the RAS plays a prominent role in its maintenance. Via autoregulation, the kidney essentially maintains constant renal blood flow over a wide range of blood pressures. This effect is mediated by the myogenic reflex and by TGF. Micropuncture studies have demonstrated that AII affects TGF, making the afferent arteriole more sensitive to TGF-signaled vasoconstriction. Vasoconstriction reduces GFR, promoting volume retention. Inhibiting the RAS via an ACE inhibitor or angiotensin receptor blocker (ARB) has the opposite effect, dampening the signals from TGF and promoting diuresis.