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Endocrinology Vol. 138, No. 6 2333-2337
Copyright © 1997 by The Endocrine Society

ARTICLES

Endothelins Stimulate Deoxyribonucleic Acid Synthesis and Cell Proliferation in Rat Adrenal Zona Glomerulosa, Acting through an Endothelin A Receptor Coupled with Protein Kinase C- and Tyrosine Kinase-Dependent Signaling Pathways

Giuseppina Mazzocchi, Gian Paolo Rossi, Piera Rebuffat, Ludwik K. Malendowicz, Anna Markowska and Gastone G. Nussdorfer

Departments of Anatomy (G.M., P.R., G.G.N.) and Clinical and Experimental Medicine (G.P.R.), University of Padua, I-35121 Padua, Italy; and the Department of Histology, Poznan School of Medicine (L.K.M., A.M.), PL-60781 Poznan, Poland

Address all correspondence and requests for reprints to: Prof. Gastone G. Nussdorfer, Department of Anatomy, Via Gabelli 65, I-35121 Padova, Italy. E-mail: ggnanat{at}ipdunidx.unipd.it


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The effects of endothelins (ET) on the proliferative activity of the rat adrenal cortex have been investigated in vivo, using an in situ perfusion technique of the intact left gland. The chemicals were dissolved in the perfusion medium, and the perfusion continued for 120 min. ET-1 concentration dependently increased the mitotic index and [3H]thymidine incorporation into DNA in the zona glomerulosa (ZG; 6- and 3-fold increases, respectively, at a 10-8 M concentration), but not in the inner adrenocortical layers, where the basal proliferative activity was negligible. The effect of 10-8 M ET-1 was blocked by the ETA receptor antagonist BQ-123, whereas the ETB receptor antagonist BQ-788 was ineffective. ET-2 and ET-3 (10-8 M) enhanced DNA synthesis in the ZG, but their effects were less intense than that of 10-8 M ET-1 and were directly related to their binding potency for the ETA receptor subtype (ET-1 > ET-2 >> ET-3). The selective ETB receptor agonists BQ-3020, IRL-1620, and sarafotoxin-6B were ineffective. The ZG proliferogenic action of 10-8 M ET-1 was reversed by both the protein kinase C inhibitor Ro31–8220 and the tyrosine kinase inhibitor tyrphostin-23; a complete blockade was obtained at a 10-6-M concentration of each inhibitor. In contrast, neither the protein kinase A inhibitor H-89 (10-5 M) nor the cyclooxygenase and lipoxygenase inhibitors indomethacin and phenidone (10-5 M) affected ET-1 action. Collectively, our findings indicate that ETs stimulate the proliferation of rat adrenal ZG cells, acting through ETA receptors coupled with protein kinase C- and tyrosine kinase-dependent signaling pathways. The results of the present study are in keeping with the view that in mammals, ZG is the proliferative layer involved in the maintenance of growth of the entire adrenal cortex and with the previous autoradiographic demonstration that ZG is the only adrenocortical layer provided with ETA receptors.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ENDOTHELINS (ET) are 21-amino acid peptides, mainly secreted by vascular endothelium. The three members of the ET family (ET-1, ET-2, and ET-3), acting via two main receptor subtypes, ETA and ETB, exert a potent vasoconstrictor and pressor activity (for a review, see 1 .

ET-1 as well as ETA and ETB receptors are expressed in the human and rat adrenal glands (2, 3, 4). The available evidence indicates that ETs exert a marked acute secretagogue action on both zona glomerulosa (ZG) and zonae fasciculata and reticularis (ZF/R) of the mammalian adrenal cortex, which, at least in the rat, appears to be exclusively mediated by the ETB receptor subtype (for a review, see 5 . Accordingly, the autoradiographic quantitative analysis of [125I]ET-1 binding and its displacement by selective ligands clearly demonstrated that ETB receptors are present throughout the entire adrenal cortex, whereas ETA receptors are restricted to the ZG (3, 4, 6, 7).

The functional significance of ETA receptors located in the ZG is still enigmatic. ETs, acting via ETA receptors, exert a mitogenic effect on several cell types cultured in vitro (for a review, see 1 . In vivo studies carried out in the rat showed that ET-1 stimulates the hypertrophy and proliferation of ZG cells (8, 9, 10). Hence, it does not seem unreasonable to hypothesize that ETA receptors located in the ZG may mediate this trophic effect of ET-1. However, in vivo investigations do not rule out the possibility that systemically administered ET-1 might have interacted with one or more of the extraadrenal mechanisms involved in the regulation of gland growth (e.g. kidney renin and/or pituitary ACTH release) (for a review, see 11 .

In light of these considerations, we decided to investigate the receptor subtype and the signaling mechanism mediating the in vivo proliferogenic action of ETs on the ZG by employing the technique of in situ perfusion of the isolated rat adrenal gland (12), because it allows for the delivery of the chemicals directly to the adrenal gland and the study of their effects in vivo without any possible interference with other extraglandular regulatory mechanisms.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Reagents
ET-1, ET-2, ET-3, BQ-123, BQ-788, BQ-3020, IRL-1620, and sarafotoxin-6B (S6B) were obtained from Neosystem Laboratories (Strasbourg, France). H-89, indomethacin, phenidone, colchicine, human serum albumin, and Nuclei Clean Kit were purchased from Sigma Chemical Co. (St. Louis, MO). Ro31–8220 was obtained from Roche (Milan, Italy), tyrphostin-23 from Calbiochem (Inalco, Milan, Italy), medium 199 from Difco (Detroit, MI), and [3H]thymidine from Amersham Laboratories (Aylesbury, UK).

In situ adrenal perfusion
Adult male Wistar rats (260 ± 30 g BW) were purchased from Charles River (Como, Italy). They were anesthetized with nembutal, and their left adrenal glands were perfused in situ, as described by Vinson et al. (12). Briefly, perfusion medium was introduced, via a cannula inserted in the coeliac artery, into an isolated segment of aorta from which the adrenal arteries arise; after flowing through the adrenal gland, medium was collected by a cannula inserted in the renal vein. Perfusion medium [medium 199 and Krebs-Ringer bicarbonate buffer (2:1, vol/vol) containing 0.2% glucose and 5 mg/ml human serum albumin] was gassed with 95% O2 and 5% CO2, maintained at 37 C, and delivered at a constant rate of 2 ml/10 min for 120 min. The following chemicals were added to the perfusion medium: 1) ET-1 (from 10-12-10-8 M); 2) 10-8 M ET-1 plus BQ-123 or BQ-788 (from 10-9-10-5 M); 3) 10-8 M ET-1, ET-2, ET-3, BQ-3020, IRL-1620, or S6B; 4) 10-6 M BQ-123 or BQ-788 in the presence or absence of 10-8 M ET-1, ET-2, or ET-3; 5) 10-8 M ET-1 plus Ro31–8220 or tyrphostin-23 (from 10-8-10-4 M); and 6) 10-8 M ET-1 plus 10-5 M H-89, indomethacin, or phenidone. In the case of the first perfusion experiment, in some instances, 0.1 mg colchicine dissolved in 200 µl medium was injected in the perfusion cannula at 120 min, and the perfusion continued for 60 min.

Measurement of DNA synthesis
Perfused adrenals were immediately collected under sterile conditions, gently decapsulated to separate capsule-ZG, hemisected, demedullated under the dissecting microscope, and then quartered. Adrenal capsule-ZG and ZF/R quarters were put in the perfusion medium containing 200 U/ml penicillin, 10 µg/ml streptomycin, and 2 µCi/ml [3H]thymidine. The incubation was carried out for 180 min in a shaking bath at 37 C in an atmosphere of 95% O2-5% CO2. At the end of the incubation, the medium was removed, and the samples were washed twice with ice-cold Krebs-Ringer bicarbonate buffer and frozen at -20 C. DNA was recovered from each specimen without phenol extraction and ethanol precipitation, using the Nuclei Clean Kit, and its radioactivity was measured in a liquid scintillation counter (LKB 1211, Stockholm, Sweden). Results were expressed as counts per min/100 mg tissue.

Measurement of the mitotic index
Adrenal glands of colchicine-injected rats were removed, fixed in Bouin’s solution, and embedded in paraffin. Adrenals were sectioned at 6 µm, and sections were stained with hematoxylin-eosin. For medulla-containing sections, the mitotic index (i.e. the percentage of metaphase-arrested cells) was estimated by counting 1000 cells in the ZG and ZF/R (13).

Statistics
For each experimental point five rats were perfused, and the data were expressed as the mean ± SE. Statistical comparison was performed using ANOVA, followed by Duncan’s multiple range test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
ET-1 infusion caused a concentration-dependent increase in the mitotic index and [3H]thymidine incorporation into DNA in the capsule-ZG (6- and 3-fold increases, respectively, at a concentration of 10-8 M). In the ZF/R, the mitotic index was negligible, and DNA synthesis was low; ET-1 did not affect these values (Figs. 1Go and 2Go). The ET-1 (10-8 M)-induced increase in ZG DNA synthesis was unaffected by BQ-788, whereas it was inhibited by BQ-123 in a concentration-dependent manner; a complete reversal was obtained at a concentration of 10-7 M (Fig. 3Go). Both ET-2 and ET-3 (10-8 M) enhanced DNA synthesis in the capsule-ZG, but their effects were 73% and 42% of that evoked by 10-8 M ET-1. BQ-3020, IRL-1620, and S6B (10-8 M) were ineffective (Fig. 4Go). Again, the stimulating effect of the three ETs (10-8 M) was abolished by 10-6 M BQ-123, but not by BQ-788 (Fig. 5Go).



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  		Figure 1. Effects of ET-1 on the mitotic index of rat adrenal cortex. Data are the mean ± SE (n = 5). +, P < 0.05; *, P < 0.01 [vs. the control group (C)].

 


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  		Figure 2. Effects of ET-1 on [3H]thymidine incorporation into DNA of rat adrenal cortex. Data are the mean ± SE (n = 5). +, P < 0.05; *, P < 0.01 [vs. the control group (C)].

 


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  		Figure 3. Effects of ETA and ETB receptor antagonists on the 10-8 M ET-1-induced increase in [3H]thymidine incorporation into DNA of capsule-ZG of rat adrenals. Data are the mean ± SE (n = 5). +, P < 0.05; *, P < 0.01 [vs. the control group (C)]. A, P < 0.01 (vs. baseline).

 


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  		Figure 4. Effects of 10-8 M ETs and 10-8 M ETB receptor agonists on [3H]thymidine incorporation into DNA of capsule-ZG of rat adrenals. Data are the mean ± SE (n = 5). +, P < 0.05; *, P < 0.01 [vs. the control group (C)].

 


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  		Figure 5. Effects of 10-6 M ETA and ETB receptor antagonists on basal (B) and 10-8 M ET-1-induced increase in [3H]thymidine incorporation into DNA of capsule-ZG of rat adrenals. Data are the mean ± SE (n = 5). a, P < 0.05; A, P < 0.01 (vs. the respective basal value). *, P < 0.01 (vs. the respective control value).

 
The ET-1 (10-8 M)-enhanced DNA synthesis in capsule-ZG was concentration dependently reversed by both Ro31–8220 and tyrphostin-23; a complete blockade was obtained at a 10-6-M concentration (Fig. 6Go). In contrast, 10-5 M H-89, indomethacin, or phenidone was ineffective (Fig. 7Go).



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  		Figure 6. Effects of PKC and TK inhibitors on the 10-8 M ET-1-induced increase in [3H]thymidine incorporation into DNA of capsule-ZG of rat adrenals. Data are the mean ± SE (n = 5). +, P < 0.05; *, P < 0.01 [vs. the control group (C)]. A, P < 0.01 (vs. baseline).

 


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  		Figure 7. Effects of 10-5 M PKA, CO, and LO inhibitors on basal (B) and 10-8 M ET-1-induced increase in [3H]thymidine incorporation into DNA of capsule-ZG of rat adrenals. Data are the mean ± SE (n = 5). A, P < 0.01 vs. the respective basal value.

 
When added alone to the perfusion medium, BQ-123, BQ-788, Ro31–8220, tyrphostin-23, H-89, indomethacin, and phenidone did not evoke any significant change in [3H]thymidine incorporation into DNA of capsule-ZG ( Figs. 5–7GoGoGo).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our present findings, obtained with two different technical approaches, confirm that ET-1 exerts a clear-cut mitogenic effect on rat ZG in vivo, acting directly on the adrenal glands. In addition, they indicate that the proliferogenic action of ET-1 is mediated by the ETA receptor subtype. In fact, the selective ETA antagonist BQ-123 (14), but not the specific ETB antagonist BQ-788 (15), is able to block this ET-1 effect. Addition to the perfusion medium of BQ-123 alone does not evoke per se any apparent effect, thereby making unlikely the possibility of a toxic nonspecific action of this antagonist.

The specific and exclusive involvement of ETA receptors in the mediation of the proliferogenic action of ETs on rat ZG is also supported by (and in keeping with) the following findings: 1) the selective and potent agonists of ETB receptors BQ-3020, IRL-1620, and S6B (16) do not exert any mitogenic action on rat ZG; and 2) the intensity of the stimulatory action of equimolar concentrations of ET-1, ET-2, and ET-3 on ZG DNA synthesis is directly related to their binding potencies for the ETA receptor subtype, i.e. ET-1 > ET-2 >> ET-3 (1, 16).

Our results accord well with available evidence indicating that ETA mediates the growth effect of ETs on cultured vascular smooth muscle cells (VSMC) (17, 18, 19) and Chinese hamster ovary cells transfected with ETA gene (20). However, they are in contrast with the observation that ET-1, probably via ETA receptors, exerts a marked antimitogenic effect on cultured bovine adrenocortical cells (21). Apart from obvious interspecific differences between rats and calves, this discrepancy may be explained by taking into account that striking differences in the physiology of adrenocortical cells between in vivo conditions and in vitro cultures, especially as far as their proliferative activity is concerned. For instance, ACTH, which exerts a powerful mitogenic action on the adrenal cortex in vivo, induces the functional differentiation of adrenocortical cells cultured in vitro, but simultaneously inhibits their proliferative activity (for a review, see 11 .

Our results indicate that ET-induced activation of ETA receptors elicits the proliferation of rat ZG cells through both the protein kinase C (PKC) and tyrosine kinase (TK) pathways, since both the PKC inhibitor Ro31–8220 (22) and the TK inhibitor tyrphostin-23 (23) are able to reverse the ET-1 effect. In this connection, it must be recalled that recent evidence indicates that the activation of both PKC and TK also mediates the acute secretagogue action of ET-1 in rats (24). We observed that both the PKC and TK inhibitors, when infused at 10-6 M, are able to abolish the stimulatory effect of ET-1 on ZG DNA synthesis, suggesting that a tight link exists between these two signaling systems. In fact, it is well demonstrated that the activation of phosphatidylinositol cascade and PKC plays a key role in the activation of TK (for a review, see 25 . Accordingly, PKC activation was found to stimulate TK activity in bovine and rat ZG cells (26, 27). Our present study does not provide evidence elucidating the intracellular mechanism(s) coupling ETA receptors to PKC activation. However, preliminary findings (data not shown) strongly suggest that phospholipase C plays a pivotal role; in fact, the infusion of the phospholipase C antagonist U-73122 (28, 29) at a 10-6-M concentration abolished the proliferogenic action of 10-8 M ET-1 on ZG.

Other signaling pathways that are known to mediate the mitogenic action of the main adrenoglomerulotropic hormones do not appear to be involved in the proliferogenic action of ETs. The most potent in vivo stimulator of ZG mitotic activity, ACTH, mainly acts via adenylate cyclase and PKA pathway (for a review, see 30 . Cyclooxygenase (CO) and lipoxygenase (LO) pathways of arachidonic acid have been reported to mediate the proliferogenic action of angiotensin II on rat ZG (31) and cultured bovine adrenocortical cells (32). We have presently shown that neither the PKA inhibitor H-89 (33) nor the CO and LO inhibitors indomethacin and phenidone (32) affect the ET-1-induced increase in ZG DNA synthesis, thereby ruling out the possibility that these signaling pathways may play a major role in the mechanism underlying the proliferogenic action of ETs on rat adrenal ZG, at least under our experimental conditions.

Our investigation does not allow us to ascertain the exact nuclear signal transduction mechanism by which the ET-induced activation of PKC and TK enhances ZG DNA synthesis. We wish now to briefly summarize findings that are in agreement with our results and could help us to address this issue. Compelling evidence indicates that one of the mechanisms linking hormone-receptor interaction with mitogenic effect is the induction of transcription regulatory proteins, which, in turn, modulate the activity of other regulatory genes, including those of the fos/jun family; protooncogene proteins eventually mediate the growth action of the hormones (for a review, see 34 . The mitogen-activated protein kinase (MAPK) cascade is now a well recognized important pathway of these sequential responses; MAPK can phosphorylate protooncogene proteins (35, 36), thus playing a pivotal role in G0 to G1 and G2 to M transition of the cell cycle (37). TK-activated MAPK is today considered the mediator of many physiological cell responses to several growth factors (38, 39, 40). ET-1 has been found to activate MAPK cascade in cultured cardiocytes, VSMC, and mesangial cells (41, 42, 43) and to raise levels of messenger RNA of the fos/jun gene family in rat fibroblasts and VSMC; this last effect is mediated by TK (44, 45). The demonstration that PKC and TK are both involved in the angiotensin II- and fibroblast growth factor-2-induced stimulation of MAPK in bovine adrenocortical cells (46) makes reasonable the hypothesis that a similar mechanism may underlie the proliferogenic effect of ETs on rat ZG.

In conclusion, our present study has shown that ETs, acting via ETA receptors coupled with PKC and TK intracellular signaling systems, exert a marked proliferogenic action specifically directed on the ZG. According to the cell migration theory (for a review, see 11 , ZG in mammals is the "cambium" layer involved in adrenocortical cell renewal; hence, the hypothesis can be advanced that ET-1 may enhance growth of the entire adrenal gland. The physiological relevance of this effect of ETs remains to be confirmed. According to Nussdorfer (47), the demonstration that endogenous ETs are involved in the maintenance of adrenal growth would require that ETA receptor antagonists were able per se to depress the proliferative activity of ZG, which does not occur in our experiments. However, it must be noted that basal DNA synthesis and the mitotic rate of adrenal ZG are too low for a 120- to 180-min exposure to BQ-123 (like that allowed by our in situ perfusion model) to evoke sizable significant changes in them. The study of the in vivo effect of a prolonged BQ-123 administration on the adrenal growth of rats with pharmacologically interrupted pituitary-adrenal axis and renin-angiotensin system may help us to address this issue.

Received December 19, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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