Circulation Research. Review. An Official Journal of the American Heart Association. What Signals the Kidney to Release Renin?

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1 Circulation Research MARCH VOL. XXVIII An Official Journal of the American Heart Association 1971 NO. 3 Review What Signals the Kidney to Release Renin? By James 0. Davis Much has been said and much has been written on the renin-angiotensin-aldosterqne system but one of the most important problems remains unresolved. The specific signals perceived by the renal juxtaglomerular (JG) cells to secrete renin are still unknown. In an editorial in 1964 (1), attention was called to the paucity of experimentation in this area. There is now no lack of interest in and pursuit of this important problem, and recently a number of innovative approaches have resulted in pertinent new data. This article is written to describe these new approaches and to stimulate interest and further research which might close this important gap in our knowledge. Early attempts at elucidation of this problem were aimed at testing either the baroreceptor hypothesis or the macula densa theory. Increasing evidence has accumulated to support the idea that the sympathetic nervous system is also involved. And, a number of humoral agents influence renin release, espe- - dally in pharmacologic doses; these findings raise the question of the physiological roles of these substances in the control of renin secretion. The JG cells, the macula densa, and the renal sympathetic nerves are depicted diagrammatically in relation to the - renal arterioles (Fig. 1). In homeostasis and in several experimental and clinical situations with secondary aldosteronism, the renin-angiotensin-aldosterone From the Department of Physiology, University of Missouri School of Medicine, Columbia, Missouri Received November 16, Accepted for publication January 12, system plays a primary role in control of body fluid volume. This control problem may be posed in terms of the so-called "volume receptor" which represents the afferent limb of a more complex receptor-effector system. According to the baroreceptor hypothesis, the renal afferent arterioles and JG cells respond to changes in stretch which could be secondary to changes in vascular volume and pressure. This idea was first proposed by Tobian et al. in 1959 (2) and received support from experiments of Skinner et al. (3). The JG cells might perceive (1) a change in intravascular afferent arteriolar pressure, (2) an alteration in the transmural pressure gradient across the afferent arteriole which could be mediated by a change in either intravascular pressure or renal interstitial pressure, or (3) a change in wall tension in the afferent arteriole by an alteration either in the transmural pressure gradient or in the diameter of the.arteriole according to Laplace's law. Until recently, evidence has been lacking to provide the crucial data for the existence of an intravascular receptor which might respond to changes in stretch. A new approach to evaluation of the baroreceptor hypothesis has been the use of the nonfiltering, denervated kidney model in adrenalectomized dogs (4, 5). In this preparation, the macula densa is rendered nonfunctional, the renal nerves are eliminated, and the major part of the circulating catecholamines is excluded. With no glomerular filtration, there is no movement of fluid past the macula densa so that changes in sodium load or concentration secondary to hemorrhage or aortic constriction cannot occur in the usual manner. Circulation Research, Vol. XXVIU, March

2 302 DAVIS GLOMERULUS FIGURE 1 Diagram of the juxtaglomerular apparatus. The two possible receptors, the JG cells of the afferent arteriole and the macula densa, are depicted in their close physical relationship. According to the baroreceptor hypothesis, the JG cells respond to changes in vascular volume and pressure, and renin is released. Also, a change in sodium load or sodium concentration might provide the signal for stimulation of the macula densa with a resultant influence on renin release. The JG cells secrete renin into the lumen of the renal afferent arteriole and into renal lymph. The renal nerves are depicted as ending in both the JG cells and the smooth muscle cells of the renal afferent arteriole. Attention is also called to the intimate relationship of the efferent arteriole and macula densa; granular cells have been observed, but rarely, in the efferent arteriole. In this nonfiltering kidney model, a striking increase in renin secretion was observed in response to both hemorrhage and suprarenal aortic constriction. The data support the concept of an intravascular receptor located in the renal vascular tree. It seems Likely that this receptor is localized in the renal afferent arterioles. Since the observed increases in renin secretion were associated with decreased renal perfusion pressure and renal blood flow and reinfusion of blood during a recovery period decreased plasma renin activity to the control level, the observations are consistent with a baroreceptor mechanism. Additional evidence that the degree of constriction of the renal arterioles is important in renin release was provided from studies of experimental renal hypertension in dogs. Ayers et al. (6) reported that chronic renal artery constriction, produced an initial dilatation followed by gradual constriction of the renal arterioles. The initial decrease in renal arteriolar resistance was associated with increased plasma renin activity, and progressive Circulation Research, Vol. XXVIII, March 1971

3 MECHANISMS OF RENIN RELEASE 303 constriction of the renal arterioles later was accompanied by a return in plasma renin activity to normal; systemic arterial pressure remained elevated. Vasodilator d r ugs such as dopamine, isoproterenol, nitroprusside and aeetyleholine increased renin release in renal hypertensive dogs with little effect on normal animals. Changes in neither arterial pressure per se nor sodium excretion were correlated with alterations in renin release. Numerous attempts have been made to provide evidence that the macula densa is a primary sensing element in the renin release mechanism. Available data support this concept, but there is no agreement about the specific signal perceived by the macula densa. One school of workers has favored the view that a decrease in sodium load at the macula densa leads to renin release. This hypothesis originated with the classic experiments of Vander and Miller (7), who prevented an increase in renin secretion following aortic constriction by administration of diuretics; presumably, this was associated with an increase in sodium load at the macula densa. Recently, Vander and Carlson (8) have been more specific in suggesting that renin release is mediated by decreased sodium transport by the macula densa cells. Another school originated with the micropuncture experiments of Thurau and associates (9), who maintained that it is an increase in sodium load or concentration at the macula densa that promotes renin release. This view is also supported by the findings of Cooke et al. (10), who showed that ethacrynic acid, an inhibitor of sodium reabsorption in Henle's loop, increased renal venous renin activity within 5 minutes after drug administration and that the renin response occurred in the absence of volume depletion; reinfusion of ureteral urine into the femoral veins prevented volume depletion. In contrast, chlorothiazide, which acts on the distal nephron and has little effect on Henle's loop, failed to increase renin release during reinfusion of urine. These and other experiments led Cooke and associates to propose that increased sodium concentration at the macula densa leads to renin release. Similar experiments in rabbits during furosemide administration and the absence of volume depletion led Meyer et al. (11) to the same hypothesis. Nash (12) has proposed that a "tubular natriastat" perceives a signal leading to renin release. Measurements are needed to assess precisely what does occur to sodium transport in the macula densa under various experimental conditions. Available methodology has not been adequate to provide this information. Several workers have considered the possibility that an intrarenal feedback mechanism exists between the macula densa and the glomerulus within each nephron. This intermediate functional connection was suggested by Guyton (13) in a computer model for renal autoregulation. The micropuncture experiments of Thurau and coworkers (9) supported the idea with the observation that hypertonic sodium solutions injected in a retrograde manner from the distal tubule into the macula densa produced proximal tubular collapse. They reasoned that angiotensin II is formed locally in the JG cells, is released into the afferent arteriolar lumen, and produces afferent arteriolar constriction with a reduction in GFR. The concept also implies that the decrease in GFR leads to a decrease in sodium concentration at the macula densa with a resultant decrease in renin release to complete the feedback loop. The hypothesis has been championed by Thurau and coworkers (14), who reported that angiotensin II can be formed locally in the JG cells. Observations of several other workers have failed to support this hypothesis. Nevertheless, it is an attractive idea and new data on this concept will probably be forthcoming. The importance of changes in plasma potassium concentration in the control of renin secretion was first recognized by Veyrat and associates (15). Others have subsequently investigated this relationship in detail and found that changes in plasma renin activity occurred independent of associated alterations in either aldosterone secretion (16) or in sodium balance (17). Available data are consistent with an intrarenal action of potas- Circulation Research, Vol. XXVlll, March 1971

4 304 DAVIS sium, and this effect could be mediated by (1) changes in sodium load or concentration at the macula densa, (2) a direct action on the JG cells, or (3) a direct action on renal arteriolar smooth muscle cells. Evidence for the role of the renal nerves in the release of renin has come from several sources. Vander (18) reported that electrical stimulation of the renal nerves released renin, and the response in renin release to hemorrhage appears to be mediated, at least in part, by the renal sympathetic nerves. Gordon et al. (19) pointed out that increased physical activity and its effect to increase plasma renin activity is mediated by the renal sympathetic nervous system. Additional evidence that the renal nerves play an important role in renin release during changes in sodium balance was provided by Mogil et al. (20). They demonstrated that plasma renin activity failed to increase in response to sodium depletion in dogs with renal denervation. Although substantial evidence has accumulated for a role of the renal nerves in renin release, the precise mechanisms involved remain unknown. The renal nerves might (1) produce changes in the degree of afferent arteriolar constriction and thereby stimulate baroreceptors in the JG cells, (2) influence directly the release of renin since terminal nerve endings of the renal sympathetic nerves have been observed in the JG cells, or (3) decrease GFR and change the sodium load or concentration at the macula densa. Tobian (21) offered the provocative suggestion that the renal nerves might amplify signals to the JG cells so that they are more sensitive to small changes in pressure and volume. Observations are needed under conditions where the experimental design allows only one of these alternative hypotheses to be examined at a time so that more conclusive data can be obtained. Wathen and associates (22) demonstrated that intravenous and intrarenal arterial infusion of epinephrine and norepinephrine increased renin release in amounts of these catecholamines sufficient to decrease renal hemodynamic function. More recently, Michelakis et al, (23) reported that "net renin production" was increased by epinephrine, norepinephrine, and cyclic AMP in dog renal cell suspensions. Assaykeen and associates (24) carried out studies which point to a physiological role of the adrenal medulla in the regulation of renin secretion. They induced hypoglycemia with insulin, increased the plasma level of epinephrine, and observed an increase in plasma renin activity. In more recent unpublished observations by this group, reproduction of the same plasma level of epinephrine by infusion of this hormone gave less of an increase in plasma renin activity and more of an increase in arterial pressure than observed with hypoglycemia. Their findings raise the possibility of some as yet undefined adrenal medullary influence, since norepinephrine was excluded as the causative agent in these experiments. The role of adrenergic receptors has been studied by Winer and associates (25). In normal subjects, plasma renin activity was increased by diazoxide, ethacrynic acid, and theophylline, which probably act as stimuli through diverse mechanisms; their influence on sodium excretion was quite variable. With each stimulus, plasma renin activity was decreased on retesting when either phentolamine or propranolol was given; furthermore, adrenergic blockade had little influence on sodium excretion. These findings and the work of Assaykeen et al. (24) suggest a physiological role for the sympathetic nervous system and catecholamines in renin release. Studies are needed to determine the effects of epinephrine, norepinephrine, and various other humoral agents on the biosynthetic mechanisms for renin as well as on renin release. Available evidence thus provides support for (1) the existence of both a renal vascular receptor and a macula densa receptor, (2) a role of the renal sympathetic nerves, and (3) the action of various humoral agents including sodium and potassium ions, angiotensin II, and the catecholamines. A plausible working hypothesis is that both receptors are operative but that the extent of dominance varies with the physiological or pathophysi- CircuUUon Research, Vol. XKVlll, March 1971

5 MECHANISMS OF RENIN RELEASE 305 ological conditions. The observations of Blaine et al. (4,5) on the functional autonomy of the baroreceptor cells may reflect the fundamental nature of this mechanism. Studies are needed to define the precise signal perceived by the vascular receptor and to determine the functional changes in renal tubular fluid composition or flow which activate the macula densa. It is still uncertain what changes in sodium transport occur in the macula densa to alter renin release. Also, the intermediate link between both receptors and the JG cells remains unknown. The juxtaposition of the macula densa to the JG cells suggests the possibility of a local hormone that is released by the macula densa and diffuses into the JG cells with the subsequent release of renin. In contrast, it is conceivable that the JG cells themselves respond as a vascular receptor and that no intermediate link exists for the baroreceptor mechanism. It would be helpful to have observations which define more specifically the locus of the intravascular receptor. Also, the physiological role of humoral agents is unclear, and studies are needed to define the minimal plasma levels at which they are effective. It seems likely that the renal nerves modulate the control of renin secretion. References 1. DAVIS, J.O.: Two important frontiers in renal physiology. Circulation 30:1-6, TOBIAN, L., TOMBOULIAN, A., AND JANECEK, J.: Effect of high perfusion pressures on the granulation of juxtaglomerular cells in an isolated kidney. J Clin Invest 38: , SKINNER, S.L., MCCUBBIN, J.W., AND PAGE, I.H.: Control of renin secretion. Circ Res 15:64-76, BLAINE, E.H., DAVIS, J.O., AND PREWITT, R.: Renin release from the denervated, nonfiltering dog kidney (abstr). Amer Fed Clin Res 18:494, BLAINE, E.H., AND DAVIS, J.O.: Evidence for a renal vascular mechanism in renin release: New observations with graded stimulation by aortic constriction. Circ Res Suppl, in press. 6. AYEBS, C.R., HARMS, R.H., JR., AND LEFER, L.G.: Control of renin release in experimental hypertension. Circ Res 24 (suppl I): , Circulation Research, Vol. XXV U I, March VANDER, A.J., AND MILLER, R.: Control of renin secretion in the anesthetized dog. Amer J Physiol 207: , VANDER, A.J., AND GABLSON, J.: Mechanism of the effects of furosemide on renin secretion in anesthetized dogs. Circ Res 25: , THURAU, K., SCHNERMANN, ]., NACEL, W., HORSTER, M., AND WOHL, M.: Composition of tubular fluid in the macula densa. segment as a factor regulating the function of the juxtaglomerular apparatus. Circ Res 21 (suppl II): II , COOKE, C.R., BROWN, T.C., ZACHERLE, B.J., AND WALKER, W.G.: Effect of altered sodium concentration in the distal nephron segments on renin release. J Clin Invest 49: , MEYER, P., MENARD, J., PAPANICOLAOU, N., ALEXANDRE, J.M., DEVAUX, C, AND MILLIEZ, P.: Mechanism of renin release following furosemide diuresis in rabbit. Amer J Physiol 215: , NASH, F.D.: Renin release: Further evidence for the role of a tubular natriastat. Amer Soc Nephrol Abstracts, p. 51, GUYTON, A.C., LANGSTON, J.B., AND NAVAR, B.: Theory of renal autoregulation by feedback at the juxtaglomerular apparatus. Circ Res 15 (suppl I): , THURAU, K., DAHLHEIM, H., AND GRANGER, P.: On the local formation of angiotensin at the site of the juxtaglomerular apparatus. Proc 4th Int Cong Nephrol 2:24-30, Basel, Karger, VEYRAT, R., BRUNNER, H.R., MANNING, E.L., AND MULLER, A.F.: Inhibition de l'activite de la renine plasmatique par le potassium. J Urol Nephrol (Paris) 73: , BRUNNER, H.R., BAER, L., SEALEY, J.E., LEDINGHAM, J.G.G., AND LARACH, J.H.: Influence of potassium administration and of potassium deprivation on plasma renin in normal and hypertensive subjects. J Clin Invest 49: , ABBRECHT, P.H., AND VANDER, A.J.: Effects of chronic potassium deficiency on plasma renin activity. J Clin Invest 49: , VANDER, A.J.: Effect of catecholamines and the renal nerves on renin secretion in anesthetized dogs. Amer J Physiol 209: , GORDON, R.D., KUCHEL, O., LIDDLE, G.W., AND ISLAND, D.P.: Role of the sympathetic nervous system in regulating renin and aldosterone production in man. J Clin Invest 46: , MOCIL, R.A., ITSKOVTTZ, H.D., RUSSELL, J.H., AND

6 306 DAVIS MURPHY, J.J.: Renal innervation and renin activity in salt metabolism and hypertension. Amer J Physiol 216: , TOBIAN, L.: Renin release and its role in renal function and the control of salt balance and arterial pressure. Fed Proc 26:48-54, WATHEN, R.L., KINGSBURY, W.S., STOUDER, D.A., SCHNEIDER, E.G., AND ROSTORFER, H.H.: Effects of infusion of catecholamines and angiotensin II on renin release in anesthetized dogs. Amer J Physiol 209: , MICHELAKIS, A.M., CAUDLE, J., AND LIDDLJE, G.W.: In vitro stimulation of renin production by epinephrine, norepinephrine, and cyclic AMP. Proc Soc Exp Biol Med 130: , ASSAYKEEN, T.A., OTSUKA, K., GOLDFIEN, A., AND GANONG, W.F.: Effect of hypoglycemia on circulating renin levels. Excerpta Med Int Cong, Ser 157, 1968, abstr WINER, N., CHOKSHI, D.S., YOON, M.S., AND FREEDMAN, A.D.: Adrenergic receptor mediation of renin secretion. J Clin Endocr 29: , OrcuUaiim Rneatcb, Vol. XXVIII, March 1971