Renal Effects

I. Summary_

Amylin bound to kidney cortex in a distinctive pattern. Binding appeared specific in that it was displaceable with amylin antagonists. It was associated with activation of cyclic AMP (cAMP), and was thereby likely to represent receptor binding and activation. Amylin's principal effects at the kidney included a stimulation of plasma renin activity, reflected in aldosterone increases at quasi-physiological amylin concentrations. It was unclear whether this was a local or a systemic effect. Other renal effects in rats included a diuretic effect and a natriuretic effect. The latter was mainly driven by the diuresis, since urinary sodium concentration did not change.

Amylin had a transient effect to lower plasma potassium concentration. This effect was likely to be a consequence of activation of Na+/K+-ATPase, an action shared with insulin and catecholamines. Amylin lowered plasma

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calcium, particularly ionized calcium, likely due to an antiresorptive effect at osteoclasts.

Immunoreactive amylin was detected in the developing kidney. It appeared to have a trophic effect in kidney, and its absence resulted in renal dysgenesis.

Neurons in the subfornical organ (SFO), which has a role in fluid/ electrolyte homeostasis, were potently activated by amylin. The dipsogenic and renal effects of amylin may be related to effects at the SFO.

II. Renovascular Effects_

The first report of an amylin action at the kidney was renal vasodilation, described in Chapter 14 of this volume (Gardiner et al., 1991). These actions were attributed to occur via calcitonin gene-related peptide 1 (CGRP1) receptors (Chin et al., 1994; Hall and Brain, 1993) and were not blocked with the amylin receptor antagonist AC187 (Haynes et al., 1994).

III. Amylin Binding in Kidney_

The possibility of a direct effect of amylin at the kidney was raised when it was noted that it bound to kidney (Cooper et al., 1992) in a pattern that appeared distinct from that of calcitonin or CGRP (Wookey et al., 1996). The greater potency of the amylin antagonists AC66, AC413, and AC187 over hCGRP[8-37] in displacing labeled amylin indicated that the binding sites exhibited an amylin-like pharmacology (Haynes et al., 1994; Wookey et al., 1994a,b). Using labeled AC512 (an amylin antagonist that can bind to fixed tissue), Dilts et al. obtained a similar pattern of cortical, largely renotubular binding (Dilts et al., 1995). Amylin binding at the kidney increased in the spontaneous hypertensive rat (SHR) and in surgically induced rat models of hypertension (Wookey et al., 1997) but was not reduced by normalization of blood pressure with angiotensin converting enzyme inhibitors (Cao et al., 1997), prompting an interpretation that amylin was somehow associated with blood pressure control. In the monkey, amylin also bound to the renal cortex (Cooper et al., 1995a). In rats and monkeys, amylin bound to tubules (Chai et al., 1998; Wookey et al., 1996).

But since renal tubules are dense with proteases, it was unclear whether such binding was to receptors or to an enzymatic site. The observation that amylin could stimulate cAMP production in kidney slices indicated a receptor-mediated effect somewhere in the kidney (Sexton et al., 1994; Wookey et al., 1996). At cloned pig kidney calcitonin receptors (Lin et al., 1991), amylin stimulated cAMP production as potently as did calcitonin, and since it circulates at greater concentrations than calcitonin, it may be a cognate ligand for such kidney receptors (Sexton et al., 1994). In the monkey, amylin

FIGURE 1 Binding of amylin, CGRP, and salmon calcitonin to rat kidney, showing distinctive cortical (glomerular) binding of 125I-amylin. Images courtesy of Prof. Mark Cooper.

binding could be localized to the juxtaglomerular apparatus (Chai et al., 1998; Sexton et al., 1995), suggesting a possible effect in the renal renin-angiotensin system (Fig. 1).

IV. Effects on the Renin-Angiotensin-Aldosterone


The first indication that amylin might affect the renin-angiotensin system was a doubling of plasma renin activity within 30 min of subcutaneous injection of 100 mg amylin in anesthetized rats (Young et al., 1994c). Falls in blood pressure, which can themselves stimulate renin secretion, did not occur with this subcutaneous dose of rat amylin. The effect could be blocked with the amylin receptor blockers AC66, AC187 (Young et al., 1994a), and AC625, pointing to an action mediated via an amylin-like receptor. The effect was not blocked with propranolol, indicating that it was independent of sympathetic activation (Young et al., 1994c).

In human subjects, human amylin administered as primed/continuous infusions increased plasma renin activity by up to 97% (Cooper et al., 1995b; McNally et al., 1994) and, at some infusion rates, human amylin also increased aldosterone concentration by up to 62% (Nuttall et al., 1995a,b; Young et al., 1995). No change in blood pressure or plasma sodium concentration occurred at any dose (Young et al., 1995).

A. Potency of Effect

Initial dose-response studies (Smith et al., 1994; Young et al., 1995) suggested that the effect could prevail at the elevated plasma amylin concentrations observed in insulin-resistant individuals. However, dose responses for effects on renin secretion were not performed in insulin-resistant animals (or humans). Since amylin resistance can be a concomitant feature of insulin resistance (as determined, for example, in effects on gastric emptying, described in Chapter 6), it should not be presumed that amylin concentrations that increase renin activity in insulinsensitive individuals will do the same in insulin-resistant (hyperamylinemic) individuals.

B. Pharmacology of Effect

Increases in plasma renin activity with amylin in animals and humans are similar in magnitude and character to those reported for salmon calcito-nin (Clementi et al., 1986; Malatino et al., 1987) and CGRP (both amylin agonists) (Braslis et al., 1988; Gnaedinger et al., 1989; Kurtz et al., 1988; Palla et al., 1995b). Concordance of effects of amylin, salmon calcitonin, and CGRP suggested an amylin-like pharmacology.

C. Hypothesis Linking Excess Amylin Action to Hypertension

The observation that amylin agonists could stimulate renin secretion led to the proposal that excess amylin action (for example, in hyperamylinemic insulin-resistant individuals) could contribute to obesity-related hypertension (Young et al., 1994b). Others have since made similar speculations (Cooper, 1997; Cooper et al., 1995b; Haynes et al., 1997; Williams, 1994; Wookey and Cooper, 1998; Wookey et al., 1996). This hypothesis was initially attractive for a number of reasons:

1. Hyperinsulinemia is robustly associated with essential (obesity-related) hypertension (Modan et al., 1985; Welborn et al., 1966), now recognized in the term syndrome X (Reaven, 1988). And although insulin had potentially hypertensive actions (DeFronzo, 1981; Landsberg, 1989), the data linking the metabolic defects of insulin resistance with hypertension were associative rather than causal, such that the precise nature of this relationship remained unexplained (Hall, 1993; Jarrett, 1991; Lefebvre, 1993). Hyperinsulinemia per se is unlikely to be directly responsible for elevation of blood pressure (Hall, 1993; Jarrett, 1992; Lefebvre, 1993); chronic infusions of insulin either systemically or intrarenally (Brands et al., 1991; Briffeuil et al., 1992; Hall et al., 1990a,b, 1991a,b) failed to elevate blood pressure in animal models. Patients with insulinoma, although hyperinsulinemic (and not hyperamylinemic; Nieuwenhuis et al., 1992a,b), did not exhibit a propensity to be hypertensive (Pontiroli et al., 1992; Sawicki et al., 1992).

2. Agents that reduced b-cell secretion by improving insulin sensitivity, such as the thiazolidinediones (Kotchen, 1994; Yoshioka et al., 1993) and metformin (Landin-Wilhelmsen, 1992; Morgan et al., 1992), could also reduce blood pressure, as did other maneuvers that reduced b-cell secretion, including exercise (Reaven et al., 1988) and somatostatin administration (Carretta et al., 1989; Reaven et al., 1989). Conversely, maneuvers that increased b-cell secretion, such as the administration of sulfonylurea drugs (Peuler et al., 1993) or fructose feeding (Hwang et al., 1987), were reported to increase blood pressure. None of these associations distinguished between effects that might be attributable to hypersecretion of insulin versus hypersecretion of amylin.

3. While the role of plasma renin in the pathogenesis of common forms of hypertension is still debated, partly because measured renin was thought not to vary with blood pressure (Meade et al., 1983), many lines of evidence now implicate it. A study of normal weight, normotensive obese and hypertensive obese individuals (Licata et al., 1994) found plasma renin activity to be a major covariant of blood pressure. In longitudinal studies, increases in arterial pressure associated with weight gain were also associated with increases in plasma renin activity (Hall et al., 1993), while decreases in pressure associated with weight loss were associated with decreases in plasma renin activity (Tuck et al., 1981). The effectiveness of renin inhibitors, angiotensin converting enzyme (ACE) inhibitors (Laragh et al., 1977), and selective angiotensin II subtype 1 (AT1) receptor antagonists (Brunner et al., 1993) in the treatment of obesity-related hypertension also pointed to a pathogenic role for the renin angiotensin system in this condition.

4. The only patient thus far described as having a tumor secreting an amylin-like substance was discovered during investigation for unexplained hypertension (Stridsberg et al., 1992). Blood pressure returned to normal and metabolic state was ameliorated following treatment with streptozotocin. The patient died unexpectedly from a cerebral hemorrhage (Stridsberg et al., 1993).

5. Renin-angiotensin elevations of the magnitude evoked with amylin can elevate blood pressure. While an 80-fold elevation of angiotensin II was required to acutely increase arterial pressure by 50 mm Hg in rats (Lever, 1993), lesser infusions could nonetheless lead to a slower pressor response (Dickinson and Lawrence, 1963; McCubbin et al., 1965) that developed over 3-5 days (Brown et al., 1981). In contrast to the 80-fold elevation required for an acute effect, it required only a 2- to 6-fold elevation

Weeks of treatment

FIGURE 2 Absence of effect of 1 year of pramlintide administration on blood pressure in humans. From Young et al. (1999).

Weeks of treatment

FIGURE 2 Absence of effect of 1 year of pramlintide administration on blood pressure in humans. From Young et al. (1999).

of angiotensin II to increase arterial pressure 50 mm Hg by the slow pressor effect (Lever, 1993).

The hypothesis wherein excess amylin action, via the renin-angiotensin-aldosterone axis, leads to elevations of blood pressure was explored in hyperamylinemic subjects with the amylin antagonist AC625 (Bryan et al., 1995). While it blocked the effects of exogenous human amylin to stimulate renin secretion in humans, AC625 had no effect, when infused for 4 days, on blood pressure in hyperamylinemic subjects. Second, dogs made hyperinsu-linemic, hyperamylinemic, hyperreninemic, and hypertensive by fat feeding showed no effect of 1 week continuous infusion of the potent amylin antagonist AC253. Finally, in a 1-year study in 507 insulin-treated type 2 diabetic patients (body mass 90.6 ± 18.2 kg; mean ± SD), some were treated three times daily with injections of pramlintide, at doses (30, 75,150 mg three times daily) that resulted in plasma amylin activity equal to or greater than that in hypertensive individuals (up to 50 pM). There was no dose-related change in either systolic or diastolic blood pressures (Young etal., 1999) (Fig. 2).

V. Effects on Kidney Fluid and Electrolyte Excretion_

Effects of amylin infusions on renal function were determined in dose-response experiments in anesthetized rats with catheterized kidneys in which glomerular filtration rate and renal plasma flow were measured using infusions of 3H-inulin and 14C-p-aminohippuric acid (PAH), respectively. Urine flow and plasma and urinary sodium, potassium, and calcium were determined at 15 min intervals (Vine et al., 1996, 1998).

Amylin at ~52 pM increased urine flow, and at ^193 pM, it also increased sodium excretion, glomerular filtration rate, and renal plasma flow. The EC50 for the diuretic effect was 64 pM ± 0.28 log. The natriuretic effect was largely determined by the diuresis, since urinary sodium concentration changed little (Vine et al., 1998) (Fig. 3).

Renal calcium and potassium excretion were significantly elevated at plasma amylin concentrations of ~52 pM and ^193 pM, respectively. Higher concentrations of plasma amylin decreased plasma calcium and potassium and blunted urinary excretion of these electrolytes. A calciuretic effect was also described in dogs (Miles et al., 1994), but the calciuresis was not sufficient to account for the lowering of plasma calcium, which was instead attributed to a calcitonin-like inhibition of bone resorption. Thus, in the rat (Vine et al., 1998), diuresis and natriuresis appeared to be the most

FIGURE 3 Concentration responses for diuretic and natriuretic effects of rat amylin in anesthetized rats. Redrawn from Vine et al. (1998).

amylin sensitive of the renal responses tested, being present at slightly above physiological concentrations. It was possible that such effects might have annulled any sodium retention resulting from activation of the renin-angio-tensin system and thereby have accounted for no net effect on blood pressure in humans (Young et al., 1999).

The effects of amylin on the kidney are similar to those described for calcitonins, especially salmon calcitonin, which exhibited a similar pattern of effects, including a potent natriuretic effect, a diuretic effect, and an anticalciuretic effect (Blakely et al., 1997; Williams et al., 1972). The anti-calciuretic effect was apparent at physiological amylin concentrations in rats (Blakely et al., 1997).

In summary, amylin bound to kidney cortex in a distinctive pattern. Binding appeared specific in that it was displaceable with amylin antagonists. It was associated with activation of cAMP, and was thereby likely to represent receptor binding and activation. Amylin's principal effects at the kidney included a stimulation of plasma renin activity, reflected in aldoste-rone increases at quasi-physiological amylin concentrations. It was unclear whether this was a local or systemic effect. Other renal effects in rats included a diuretic effect and a natriuretic effect. The latter was mainly driven by the diuresis, since urinary sodium concentration did not change.

VI. Effects on Plasma Electrolyte Concentrations_

A. Sodium

Neither rat amylin (Vine et al., 1998) nor pramlintide (Young et al., 1996) had an effect on plasma sodium concentration in anesthetized rats.

B. Potassium

Plasma potassium measured in the same studies showed a transient decrease of about 0.4 mM within 1 hr of administration of amylin or pramlintide (Vine et al., 1998; Young et al., 1996). The character of this effect was similar to that observed with CGRP, insulin, and catecholamines, which activate Na+/K+-ATPase (Andersen and Clausen, 1993; Clausen and Flatman, 1987; Klimes et al., 1984). Amylin (Clausen, 1996) and salmon calcitonin (Andersen and Clausen, 1993) were similarly shown to activate Na+/K+-ATPase. The correction of the hyperkalemia of diabetic patients in ketoacidotic crisis with insulin has been attributed to an insulin-mediated restoration of the ionic milieu, shifting accumulated extracellular potassium to the intracellular compartment. It is likely that the transient decrease in plasma potassium with amylin agonists represents a similar phenomenon (Vine et al., 1998; Young et al., 1996), since amylin agonists did not promote urinary potassium loss.

FIGURE 4 Comparison of effects of human amylin and human calcitonin on plasma calcium concentration in rats, and on resorptive activity of isolated rat osteoclasts in vitro. Redrawn from MacIntyre (1989).

C. Calcium

An effect of amylin on plasma calcium concentration was first noted in 1989 (Datta etal., 1989b; MacIntyre, 1989), and several times since (Gilbey etal., 1991; MacIntyre etal., 1991; Young etal., 1996) (Fig. 4).

In a comparison of the effects of intravenous rat amylin, human amylin, and pramlintide in rats, a reduction in total and ionized plasma calcium of similar magnitude with each compound was observed over a 2 hr period, with values for total calcium falling from a basal level of ~2.3 mM to ~1.8 mM (Young et al., 1996). A similar result was obtained following dosage by the subcutaneous route. In an infusion study, the EC50s for decrease in ionized calcium with rat amylin and pramlintide were 130 and 97 pM, respectively (Young et al., 1996) (Fig. 5).

The potency of amylin's effects on plasma calcium is sufficient to have spawned speculation that it has a physiological role in skeletal maintenance (MacIntyre, 1989). MacIntyre (MacIntyre, 1989) proposed that the effect of calcitriol (1,25-dihydroxycholecalciferol; 1,25-dihydroxyvitamin D3; the most physiologically active metabolite of vitamin D) to stimulate b-cell secretion was consistent with a calcium regulatory role in which calcium retention by amylin augmented the effect of calcitriol to enhance calcium recuperation at renal tubules (Fig. 6).

D. Acid/Base Status

An intravenous bolus of 100 mg pramlintide resulted in no observable change in pH or pCO2 in arterial blood of rats (Young et al., 1996).

In summary, amylin had a transient effect to lower plasma potassium concentration. This effect was likely to be a consequence of activation of

-60 0 60 120 180 240 300 360 0 10 100 1,000 10,000

Minutes after starting infusion Plasma amylin concentration (pM)

FIGURE 5 Concentration response for the effect of continuously infused rat amylin to lower plasma ionized calcium in rats. Redrawn from Young et al. (1996).

-60 0 60 120 180 240 300 360 0 10 100 1,000 10,000

Minutes after starting infusion Plasma amylin concentration (pM)

FIGURE 5 Concentration response for the effect of continuously infused rat amylin to lower plasma ionized calcium in rats. Redrawn from Young et al. (1996).

FIGURE 6 Proposed integration of bone-conserving roles of calcitriol and amylin (MacIntyre, 1989).

Na+/K+-ATPase, an action shared with insulin and catecholamines. Amylin lowered plasma calcium, particularly ionized calcium, likely due to an antiresorptive effect at osteoclasts.

VII. Effects in Isolated Kidney Preparations_

Membranes from rat kidney cortex incubated with rat amylin increased cAMP production 3-fold. The amylin receptor antagonists AC187 and AC413, at tested doses, inhibited this effect, but hCGRP[8-37] did not, suggesting this effect was mediated via an amylin-like receptor (Wookey et al., 1994, 1996). CGRP[8-37] was less potent than AC413 and AC66 (sCT[8-32]) in inhibiting amylin-stimulated cyclase activity (Wookey et al., 1996) and was ^100-fold less potent in displacing 50 pM 125I-rat amylin from kidney membranes (Wookey et al., 1996).

In split-drop single-nephron micropuncture studies, and in contrast to the natriuretic effect in whole animal studies, systemically administered amylin promoted tubular sodium re-absorption by 28%, while AC187 reduced it 22% (Harris et al., 1997). The mechanism was proposed to involve Na+/H+ exchange (Hiranyachattada et al., 1995).

VIII. Effects on Kidney Development and

Endothelial Integrity_

In primary culture of rat proximal tubule cells from neonatal rat pups, amylin stimulated proliferation while the antagonists AC187, AC413, and AC512 blocked it (Harris et al., 1997). Interestingly, amylin mRNA was transiently expressed between embryo day 17 and postnatal day 7. The location of these amylin gene transcripts was below the nephrogenic zone, associated with the primitive tubules of the developing nephrons. There was no evidence of expression in the normal adult kidney. In the developing kidney (metanephros), amylin peptide could also be detected by immuno-histochemistry using a rabbit polyclonal anti-rat amylin antibody (Tikellis et al., 1997). These studies suggested that amylin could act as a growth factor in kidney development. In support of this interpretation, kidney development was found to be disturbed in amylin gene knockout mice (Wookey et al., 1999). In the cortices of the knockout mice, intertubular spaces were 4.8-fold greater than in controls (P < 0.01). These spaces were mostly lined with cells positive for the endothelial marker von Willebrand factor, thus representing a large expansion of the capillary volume. Such a picture was consistent with ''tubular drop out'' resulting from reduced expansion of developing proximal tubules, and was consistent with a role for amylin as a growth factor for the epithelial cells of the proximal tubules.

Circulating von Willebrand factor peptide, a marker from endothelial cells, distinguishes diabetic patients with nephropathy from those without it (Vischer et al., 1998). Some have proposed that the absence of nephro-active agents from the pancreatic b-cell, recently proposed to include C-peptide (Wahren and Johansson, 1998), may aggravate the course of diabetic nephropathy. It might similarly be possible that the absence of a trophic effect of amylin could be implicated in the nephropathy of insulinopenic diabetes, also characterized by lack of amylin.

Immunoreactive amylin was detected in the developing kidney. It appeared to have a trophic effect in kidney, and its absence resulted in renal dysgenesis.

IX. Effects on Subfornical Organ and

Drinking Behavior_

Fluid and electrolyte balance is controlled not only via renal excretion and effects on the renin-angiotensin-aldosterone system, but also by control of intake. Angiotensin, for example, not only evokes vasoconstriction and sodium retention in response to depletion of extracellular volume, but also stimulates thirst (Fitzsimons, 1998) via actions on the SFO, which it activates (McKinley et al., 1992). The SFO is one of the specialized ''sensory'' areas of the brain, the circumventricular organs, that also include the organ-um vasculosum lateroterminalis (OVLT) and area postrema, where a leaky blood-brain barrier allows circulating peptide hormones to access neurons (Simon, 2000). Neurophysiological investigation of SFO neuronal activity showed that 61% of cells were stimulated by calcitonin and that almost all of these were angiotensin II sensitive (Schmid et al., 1998). The effect of amylin and angiotensin II on spontaneous neuronal activity was examined using a rat SFO slice preparation. Superfusion with amylin and angiotensin II activated 72% and 69%, respectively, of the 32 SFO neurons tested for their reactivity to both peptides. The remaining neurons were insensitive; not a single neuron was inhibited. The specificity of the amylin-induced excitation was confirmed by co-application of an amylin antagonist (AC187) in a concentration 10-fold higher. AC187 totally blocked the excitatory effect (Rauch et al., 1997). Amylin activation was not blocked with losartan, an angiotensin receptor antagonist, indicating that the activation by amylin was not secondarily mediated via an angiotensinergic mechanism (Riediger et al., 1999b). The threshold concentration for amylin was below 10 nM and was thus similar to the threshold concentration observed with angiotensin II in this preparation. Concordance of amylin and angio-tensin sensitivity in the SFO prompted in vivo studies of the effect of amylin on water intake, which are described more fully in Chapter 5.

In brief, subcutaneous injection of amylin and angiotensin II in water-sated, adult male rats caused drinking in 13/17 and 16/20 rats, respectively, whereas only 6 out of 33 control rats drank during the 2 hr period following the injection. The cumulative water intake of all rats receiving amylin or angiotensin II was increased (Rauch et al., 1997; Riediger et al., 1999b). These data provided the first direct evidence of a neural substrate for prandial drinking, a phenomenon that had previously been regarded as a learned behavior (Rauch et al., 1997).

In a pharmacological study looking at effects of amylin, CGRP, rat calcitonin, salmon calcitonin, AC187, and CGRP[8-37] on SFO neuronal activity, it was observed that (1) CGRP was a weaker agonist in the SFO than amylin, (2) salmon calcitonin excites SFO neurons, and (3) responses were blocked by AC187 but not by CGRP[8-37]. As described elsewhere, this pattern was inconsistent with activation via CGRP receptors, but was instead consistent with involvement of amylin-like (C3) and/or calcitonin-like (C1) receptors (Riediger et al., 1999c).

The same authors have examined amylin action at the area postrema (described in a separate section), another circumventricular brain structure that serves as a multifunctional receptor organ and that, as an integrative structure, is also involved in the control of sodium and fluid intake (Simon, 2000). Nearly half of the neurons in this structure are amylin sensitive (Riediger et al., 1999a). Amylin may stimulate water intake by acting on the SFO and inhibit food intake by acting on the area postrema (Simon, 2000).

In summary, neurons in the SFO, which has a role in fluid/electrolyte homeostasis, were potently activated by amylin. The dipsogenic and renal effects of amylin may be related to effects at the SFO.


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