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Calcitonin Gene Products and the Kidney

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Calcitonin Gene Products and the Kidney Kiinische Klin Wochenschr (1989) 67:870-875 W°chenchrif t © Springer-Verlag 1989 Calcitonin Gene Products and the Kidney A. Kurtz 1, R. Muff z, and J.A. Fischer z 1 Physiologic Institute, University of Ziirich, Switzerland 2 Research Laboratory for Calcium Metabolism, Departments of Orthopedic Surgery and Medicine, University of Ziirich, Ziirich, Switzerland Summary. Calcitonin gene-related peptide (CGRP) Calcitonin and CGRP are single chain polypep- is localized in capsaicin-sensitive nerve fibres in the tides consisting of 32 and 37 amino acids, respec- kidney and urogenital tract whereas calcitonin tively. They have in common amino-terminal ring reaches the kidney through the general circulation. structures linked by disulfide bridges and the car- Systemic infusion of CGRP and perfusion of iso- boxyltermini are amidated. In man, CGRP shares lated rat kidney reduces vascular resistance, and 16% structural homology with calcitonin whereas increases renal blood flow and glomerular filtra- the homology between CGRP-I and -II is 92% tion. CGRP stimulates renin secretion in vivo and [13]. As a result, distinct receptors for calcitonin in vitro and inhibits contraction of isolated rat me- and CGRP have been identified [7, 11, 33, 42]. sangial cells by angiotensin II. Calcitonin does not Human CGRP-I and -II, due to their high homolo- affect vascular resistance, renal blood flow and glo- gy, crossreact almost completely, but subtle differ- merular filtration, and is tess potent in stimulating ences in the distribution of human CGRP-I and renin secretion, and does not alter contraction of -II binding sites have been observed on receptor isolated rat mesangial cells by angiotensin II. autoradiography of the human brain [22]. CGRP also exerts renal tubular effects brought Calcitonin is predominantly synthesized and re- about probably through interaction with calcitonin leased from thyroid C-cells [15]. An important sti- receptors. To this end, increased excretion of sodi- mulator of calcitonin secretion is an increase in um and chloride, and stimulation of urinary flow the extracellular calcium concentration [36]. Calci- are less pronounced with CGRP than with calcito- tonin can be considered as a hormone that reaches nin. Calcitonin, moreover, stimulates the fractional its target tissues via the circulation. Calcitonin urinary excretion of calcium and phosphate. lowers serum calcium levels through inhibition of bone resorption [37]. In the kidney, calcitonin sti- Key words: Calcitonin - Calcitonin gene-related mulates the urinary excretion of calcium, phos- peptide - Renovascular effects - Renotubular ef- phate, sodium, potassium and chloride, and en- fects - Renin secretion hances 1,25-dihydroxycholecalciferol production [5, 20, 25, 32]. CGRP is predominantly synthesized in the ner- vous system and is frequently found in peripheral Alternative splicing of the initial calcitonin gene nerves associated with blood vessels, but CGRP transcript results in the formation of two distinct has also been identified in the normal human thy- messenger RNAs encoding the precursors of calci- roid gland and in thyroid C-cells [17, 21, 41]. Much tonin and of calcitonin gene-related peptide like the secretion of calcitonin, the release of (CGRP) [2, 26]. In man and rat two calcitonin/ CGRP from C-cells is stimulated by raised extra- CGRP genes have been recognized [3, 40]. A pseu- cellular calcium concentrations [21]. In vivo serum dogene encoding a second calcitonin-like structure levels of CGRP only minimally respond to changes appears not to be expressed in man [40]. But of the extracellular calcium concentration and CGRP-I (or 7) and -II (or fl) have been identified probably largely represent a spillover from the ner- in man and rat at the mRNA and peptide levels vous system [6]. Plasma levels of CGRP are re- [3, 23, 341. duced in capsaicin-treated rats suggesting that cir- A. Kurtz et al. : CGRP and Calcitonin, and Kidney Function 871 Table 1. Effects of CGRP and calcitonin in the kidney merular filtration are increased [43]. In man and rabbits systemic infusion of CGRP reduces arterial CGRP Caleitonin pressure, and effective renal plasma and blood flow Relaxation [4, 29]. Since in vivo reduction of arterial pressure may reduce renal blood flow, effects of CGRP on Vascular smooth muscle cells + + 0 Mesangial cells + + 0 the isolated rat kidney perfused at constant pres- Ureter + + ND sure have also been examined [30]. In this prepara- tion rat CGRP-e reduces vascular resistance and Renal blood flow + " 0 blunts the vasoconstrictory effect of angiotensin Glomerular filtration rate + ~ 0 II. In the isolated perfused rat kidney CGRP more- Renin secretion + + 0 over increases the glomerular filtration rate and the glomerular filtration fraction and urinary flow Tubular function [30]. Urinary flow + ~ + + In vitro CGRP blunts the contraction of me- Fractional excretion (Na, C1) + a + + (Ca, P04) 0 -k -k sangial cells obtained with angiotensin II [30]. Re- laxation of mesangial cells by CGRP is consistent a arterial pressure maintained: ND: not done with the increased filtration fraction observed in vivo and in vitro. The effects of CGRP in isolated rat mesangial cells are presumably mediated by ra- culating CGRP originates in part from the sensory ised cAMP production, which was also observed nervous system [10]. The most prominent effects in blood vessels [12, 27]. cAMP production prob- of CGRP are on the cardiovascular system where ably mediates the dilatory effect of CGRP in me- CGRP is a potent vasodilator and exerts positive sangial cells and presumably renal vascular smooth chronotropic and inotropic actions on the heart muscle cells. Calcitonin, on the other hand, does [8, 14, 161. not affect cAMP formation in mesangial cells. Evi- In the present review we have compared the dence was obtained that CGRP does not interfere renal effects of CGRP and calcitonin in vivo and with the calcium mobilization by angiotensin II in vitro (Table 1). in mesangial cells, suggesting that the dilatory ef- fect of CGRP is caused by other mechanisms e.g. Localization of CGRP in the Kidney inactivation of the myosin light chain kinase [1, and Urogenital Tract 30]. CGRP containing nerve fibres have been localized Taken together the results demonstrate that in kidneys of rat and guinea pigs [29, 35]. Within CGRP causes vasodilation of renal blood vessels the kidney the density of CGRP positive fibres is and increases glomerutar filtration. In the absence highest in the muscular layer of the renal pelvis. of calcitonin receptors in renal glomeruli and me- Immunoreactive nerve fibres are also recognized sangial cells it would seem that CGRP exerts direct in the proximity of arteries and arterioles (includ- renovascular effects through interaction with spe- ing the juxtaglomerular apparatus) and in the per- cific receptors [29, 30, 32, 39]. iglomerular and peritubular space (Fig. 1). Reduc- tion of CGRP containing rat renal nerve fibres Renotubular Effects following treatment with capsaicin inferres a senso- ry origin [17, 29]. CGRP immunoreactive nerve Calcitonin exerts pronounced tubular effects such fibres abolished with capsaicin are, moreover, as the enhancement of the urinary fractional excre- abundant in the ureter and bladder [19]. tion of sodium, chloride, potassium, calcium and phosphate, and stimulation of urinary flow [5, 20, 32]. Renovascular Effects Tubular effects of systemic infusions of Effects of CGRP on renal blood flow and on renal hCGRP-II have been examined in humans (Gn/id- vascular resistance have been examined in vivo in inger et al., submitted for publication). The frac- man, rats, dogs and rabbits. In anesthetized rats tional excretion of sodium and chloride is raised, graded amounts of rat CGRP-~ lead to a dose- but less pronounced than with equimolar amounts dependent fall of the renal vascular resistance and of calcitonin. The urinary flow and the fractional a simultanous increase of renal blood flow, which excretion of calcium and phosphate are not af- is associated with reduced mean arterial blood fected by CGRP. Lowered excretion of sodium and pressure [44]. In the dog renal blood flow and glo- potassium and reduction of urinary flow was 872 A. Kurtz et al. : CGRP and Calcitonin, and Kidney Function Fig. 1. Immunofluorescence micrographs from rat kidney sections after incubation with antiserum to rat CGRP~. Pelvis region (a and d), cortex region (b, e, e, and f). Control animals (a-e, e, and f) and capsaicin-pretreated animals (d). A dense network of CGRP-immunoreactive nerve fibres is seen in the pelvis muscle and close to epithelium (ep) of the control rat, whereas most of the CGRP-immunoreactive nerve profiles disappeared after capsaicin treatment. CGRP-immunoreactive fibres (arrowheads) are also present around (b) small arteries (~k'), (e) among tubules, and (e and f) close to glomeruli (~) with associated arterioles. Bars, 50 gm. (From reference [29]; reproduced from the Journal of Clinical Investigation, 1988, vol 82, p 541 by copyright permission of the American Society of Clinical Investigation) found with CGRP infusions in anesthetized rats, ume and erythropoiesis. Their regulation of secre- but mean arterial blood pressure was also reduced tion by CGRP has been examined in man and rats. [44]. Interference of hypotension with tubular func- Infusions of CGRP-II in man cause increased plas- tion seems probable. In the isolated rat kidney, ma renin activity which indicates stimulation of however, perfused at constant pressure,
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